Immunotherapy for lung cancer: How does it work?

Immunotherapy for lung cancer: How does it work?

  • April 9, 2021

Lung cancer is one of the most common forms of cancer and is the leading cause of cancer deaths worldwide. Immunotherapy uses the body’s immune system to attack and kill cancerous cells.

Lung cancer accounts for nearly 25% of all cancer deaths. Immunotherapy is a treatment option for lung cancer that activates the body’s immune cells to fight the disease.

This article explores how immunotherapy works and how it treats lung cancer.

The immune system works by recognizing foreign substances in the body and destroying them. Cancer is a foreign substance in the body that the immune system should ideally identify and destroy.

However, cancer cells have found ways to evade immune system detection. One way they do this is by expressing certain proteins, known as checkpoint proteins, on their surface.

The immune system typically uses these proteins as markers to prevent it from attacking healthy cells in the body. However, cancer cells avoid detection because they express these checkpoint proteins and trick the immune system into thinking they are healthy cells.

Typically, immunotherapy disables these checkpoint proteins on the surface of the cancer cells. This causes the immune system to recognize the cancerous cells as foreign substances and mount an attack against them.

“The general way [immunotherapy] works is the same with all cancers, but lung cancer does seem to be one of the types of cancers that benefit most from immunotherapy,” Dr. Sarah Goldberg, associate professor of medicine (medical oncology) at Yale Cancer Center, CT, explained.

“These immunotherapies can work extremely well in some people with lung cancer, while others do not benefit as much. At this point, it’s not entirely clear why,” Dr. Goldberg added.

Several different types of immunotherapies available can treat individuals with lung cancer.

Immune checkpoint inhibitors

Immune checkpoint inhibitors are the primary category of immunotherapy drugs that doctors use to treat people with lung cancer. They are drugs that target and block specific immune checkpoint proteins, boosting the immune system’s response to cancer cells.

There are two classes of immune checkpoint inhibitors for lung cancer: PD-1/PD-L1 inhibitors and CTLA-4 inhibitors.

“Most of the immunotherapies approved for the management of lung cancer belong to the same family — PD-1/PD-L1 inhibitors,” Dr. Balazs Halmos, director of the Multidisciplinary Thoracic Oncology Program at Montefiore Health System and professor of medicine at Albert Einstein College of Medicine, clarified. “Another class of agents also approved but less frequently used are called CTLA-4 inhibitors. “

PD-1/PD-L1 inhibitors

PD-L1 is a checkpoint protein typically found on healthy cells. PD-1 is a receptor found on a type of immune cell called a T cell.

PD-1/PD-L1 inhibitors help keep T cells from attacking healthy cells in the body. When the protein PD-L1 attaches to the receptor PD-1, it sends signals to the T cells to leave the healthy cells alone.

However, cancer cells sometimes produce PD-L1 proteins. When this occurs, the cancer cells send “off” signals to the immune system, preventing it from attacking the cancer cells.

However, the interaction of the PD-1/PD-L1 checkpoint inhibitors disables this rogue PD-L1 protein on the cell. As a result, the receptors on the T cells do not attach to them or receive a message saying they are healthy cells. This means that the T cells identify the cancer cells as an enemy and kill them.

Sometimes, doctors can test the cancer cells to see if they carry the PD-L1 markers. This helps them predict how likely they are to respond to the PD-1/PD-L1 inhibitors.

The Food and Drug Administration (FDA) has approved the following PD-1 inhibitors:

  • nivolumab (Opdivo)
  • pembrolizumab (Keytruda)
  • cemiplimab (Libtayo)

Currently, the only two only FDA-approved PD-L1 inhibitors are atezolizumab (Tecentriq) and durvalumab (Imfinzi).

CTLA-4 inhibitors

These checkpoint inhibitors target a checkpoint protein called CTLA-4 on T cells. CTL-4 inhibitors block the protein and stop it from working. Consequently, the body releases extra T cells to attack the cancer cells.

The only FDA-approved CTLA-4 drug is ipilimumab (Yervoy).

This is a very different class of agents, basically instigating “lazy” T cells to get more active and move out of their “homes” (the lymph nodes) into the cancer microenvironment, where they are needed,” Dr. Halmos said.

“In certain types of cancer, it seems that a combination of the two types of checkpoint inhibitors can work better than just one,” Dr. Halmos continued. “Such a combination is also approved for the management of advanced PD-L1-positive lung cancers. The same combination along with chemotherapy is also approved for all types of lung cancers, including PD-L1 negative advanced lung cancers.”

A doctor typically administers checkpoint inhibitors intravenously.

In addition to immunotherapies, researchers are also investigating other treatments.

Adoptive cell therapy

Adoptive cell therapies aim to encourage the immune system to fight cancer cells. However, they do so in different ways than checkpoint inhibitors.

Two kinds of adoptive cell therapies currently under investigation are tumor-infiltrating lymphocyte (TIL) therapy and chimeric antigen receptor (CAR) T cell therapies.

“The general idea is trying to take immune cells from a patient, and either grow them outside of the body or alter them in such a way that they can be injected back into the patient and fight the cancer cells,” Dr. Goldberg, who is also research director at the Center for Thoracic Cancers, Smilow Cancer Hospital, CT, said.

“It’s a huge area of investigation right now, especially the CAR T cell therapies, as those have already demonstrated some effectiveness in people with certain kinds of lymphomas and leukemias,” Dr. Goldberg added. “Many of us are hopeful that this may be the future of immunotherapy. But so far, there’s no proof that they are effective overall in people with lung cancer.”

Cancer vaccines

Cancer vaccines are another area of investigation.

Vaccines are substances that a healthcare professional injects into a person’s body to kick off an immune response against certain infections. While doctors traditionally use vaccines to prevent diseases in healthy people, ongoing research is investigating whether and how they can treat illnesses and diseases.

“This has been a big area of investigation for decades. Some have been tested, but we have not yet seen a vaccine that is successful in people with lung cancer,” Dr. Goldberg explained. “That’s not to say there’s no hope for a vaccine treatment in the future — it’s still being studied. It might be that it needs to be combined with another immunotherapy, or it may be a case of just finding the right vaccine.”

Immunotherapy is one of several types of treatments for lung cancer. The treatment uses a person’s immune system to fight and destroy cancer cells. Unlike chemotherapy, it does not affect healthy cells, too.

A person can talk with a doctor about their treatment options to see if immunotherapy is right for them. There are also many treatments under investigation that may become available in the future.

Recruiting T cells in cancer immunotherapy

Recruiting T cells in cancer immunotherapy

  • April 8, 2021

Immunotherapies that enhance the ability of the immune system to target cancer cells have proven effective in a variety of tumor types, yet clinical responses vary across patients and cancers. The most effective immunotherapies to date are immune checkpoint blocking antibodies, which target inhibitory surface receptors expressed by T cells, particularly programmed cell death 1 (PD-1). One of the few robust correlates of clinical response to PD-1 blockade is the presence of tumor-infiltrating T lymphocytes (TILs) prior to treatment, with immune-infiltrated tumors achieving better responses than “immunedesert” tumors (1). Therefore, it has been widely assumed that PD-1 blockade reinvigorates preexisting cells within the tumor microenvironment (TME). However, recent studies of T cell dynamics suggest that the T cell response to immune checkpoint blockade (ICB) may originate outside the tumor and rely on peripheral T cell recruitment. This has important implications for patient selection, predictive biomarkers, and design of combination treatment regimens.

The site of ICB activity has historically been predicted from the expression pattern of the target inhibitory receptor and its ligand. The first immune checkpoint inhibitor that was approved for cancer targeted the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) receptor, which is primarily expressed by CD4+ effector T cells and regulatory T cells (Tregs). Given that the CTLA-4 ligand, B7, is not expressed on malignant cells but rather on antigen-presenting cells (APCs) in the lymph node, CTLA-4 blockade was predicted to act on a lymph node–resident population of CD4+ T cells, which is subsequently recruited to the tumor. Indeed, studies in mouse models and patients have demonstrated that CTLA-4 blockade induces expansion of a subset of tumor-infiltrating CD4+ T cells expressing inducible T cell costimulator (ICOS), and increased ICOS+CD4+ T cell frequency following CTLA-4 blockade correlates with clinical response (2). Given its expression, CTLA-4 blockade has also been hypothesized to deplete intratumoral Tregs; however, this has not been consistently observed in patients (2).

Several monoclonal antibodies targeting PD-1 have since been approved for the treatment of multiple cancer types. PD-1 is expressed by several subsets of activated CD8+ and CD4+ T cells and is highly expressed on exhausted CD8+ T cells that show diminished cytotoxic responses to antigens (2, 3). Moreover, the ligand for PD-1, PD-L1, is expressed by malignant cells as well as APCs, and high PD-L1 expression within the tumor can correlate with clinical efficacy (1). These data suggest that in contrast to CTLA-4 blockade, PD-1 blockade may act primarily on tumor-resident T cells. The reinvigoration of T cells in the TME, particularly exhausted T cells, was further supported by studies in mouse models of cancer and chronic viral infection, which demonstrated that PD-1 blockade could induce proliferation and effector properties in chronically stimulated T cells (3).

However, it has been difficult to reconcile this singular paradigm of PD-1 action on tumor-resident T cells with observations that suggest a systemic immune response. For example, T cell proliferation and activation are prevalent within the tumor-draining lymph node (TDLN) and peripheral blood following PD-1 blockade in mouse tumor models (4). PD-L1 blockade within the TDLN promotes tumor rejection similar to that induced by systemic therapy, and the inhibition of T cell migration prior to PD-1 blockade abrogates tumor rejection, suggesting that the TDLN may act as a reservoir of PD-1 and PD-L1 blockade–responsive, tumor-reactive T cells (4, 5). Moreover, tumor regression following PD-1 blockade in mouse models is dependent on interactions between APC-derived B7 and the T cell costimulatory receptor CD28, which occur in the lymph node (3). In particular, recent studies highlighted the importance of PD-L1 expression on classical dendritic cells (cDCs), suggesting that PD-1 blockade may act at the level of cDC-dependent T cell priming and activation (5, 6). Further profiling of human T cell responses to PD-1 blockade in melanoma patients revealed increased T cell proliferation in the peripheral blood compared with the TME, suggesting that T cells may be activated peripherally and then recruited to the tumor (7).

A systemic antitumor immune response to PD-1 blockade is further supported by synchronous regression of multiple metastatic lesions after treatment (8). Similar to the abscopal effect, which is characterized by distant responses to site-specific tumor radiotherapy (9), uniform patterns of response among individual metastases suggest that peripheral immune cells may play an important role in the clinical response to ICB (8). Genomic profiling has also demonstrated that T cell exhaustion is epigenetically fixed, suggesting that PD-1 blockade may be unable to rescue exhausted TILs (3).

A productive immune response following ICB results in the clonal expansion of tumor-specific T cells, which can be tracked across different tissues and time points by profiling T cell receptor (TCR) sequences. TCR sequencing allows for preexisting T cell clones to be distinguished from newly activated T cells recruited from distant tissues. Early efforts to profile TCR dynamics in patients receiving anti-CTLA-4 therapy revealed a broadening of the peripheral T cell tumor-reactive TCR repertoire, supporting the idea that CTLA-4 blockade may lower the threshold of the strength of TCR signaling that is required for activation (2).

Tracking of peripheral T cell clones using TCR sequencing before and after ICB demonstrated that melanoma patients with a clinical response to therapy have significantly more clonal expansion and T cell turnover following therapy compared with nonresponders (10, 11). However, whether peripherally activated T cells traffic to the tumor remained unclear. Profiling of phenotypic and clonal T cell dynamics in site-matched human basal and squamous cell carcinomas before and after PD-1 blockade revealed that CD8+ T cells with an exhausted phenotype are more clonally expanded relative to other TILs and also expressed surface markers characteristic of tumor-reactive T cells (12). Clonal expansion of exhausted T cells in response to therapy was predominantly derived from T cell clones that were not detected in the tumor prior to therapy, and this effect was specific to exhausted T cells. Notably, most preexisting intratumoral T cell clones could be found in the tumor after therapy but did not clonally expand, and preexisting exhausted T cell clones did not adopt a nonexhausted phenotype following treatment (12). This suggests that preexisting exhausted TILs may have limited reinvigoration potential and that clonal replacement of TILs from tumor-extrinsic sources is a major aspect of ICB responses.

The cancer-immunity cycle of immune checkpoint blockade response

Immune checkpoint blockade with anti–programmed cell death 1 (anti–PD-1) therapy blocks inhibitory signaling on T cells. The immune response to PD-1 blockade relies on invigoration of tumor-extrinsic T cells during T cell priming and activation within the tumor-draining lymph node (TDLN). Activated T cells traffic to the tumor where they kill cancer cells and release antigens that are presented to T cells by dendritic cells in the TDLN, linking tumor-resident and tumor-extrinsic immune responses.

GRAPHIC: C. BICKEL/SCIENCE

Additional support for this role of tumor-extrinsic T cells comes from two studies tracking T cell clones in tumor, normal adjacent tissue, and peripheral blood. In lung, endometrial, colorectal, and renal cancers, expanded T cell clones within the tumor were commonly shared with adjacent normal tissue and peripheral blood (13). TIL clones with an exhausted phenotype were less likely to be detected in peripheral blood, suggesting that replenishment of TILs with peripheral T cells may provide a source of nonexhausted TILs. Furthermore, deep TCR profiling during neoadjuvant PD-1 blockade (prior to surgical resection) demonstrated that T cell clones that expanded in the peripheral blood following treatment were enriched within the tumor of responding patients, suggesting that expansion and subsequent infiltration of peripheral T cells may be associated with clinical response (14).

Together, these studies support a model of tumor-extrinsic T cell responses to PD-1 blockade (see the figure). Interactions between PD-L1+ cDCs and T cells in the TDLN are a compelling target for PD-1 blockade (5, 6). After priming and activation, T cells can circulate in the peripheral blood and traffic to the primary tumor site, as well as metastases. Upon cancer cell killing, the release of tumor antigens and their subsequent presentation by migratory DCs in the TDLN provide a link between the tumor-extrinsic T cell response and the cancer-immunity cycle (1). It is important to note that the tumor-extrinsic T cell response to PD-1 blockade and the reactivation of preexisting TILs are not mutually exclusive and may represent complementary or synergistic mechanisms of response.

Despite these advances, many questions remain. Although T cell clones that respond to PD-1 blockade can be found in the peripheral blood and TDLN, several possibilities regarding their precise site of activation are possible: clonal T cell priming and expansion in the TDLN and/or tertiary lymphoid sites followed by recruitment to the tumor; activation and expansion of a recently primed or unexpanded pool of progenitor T cells (such as stem cell memory or progenitor exhausted cells) within the TME and/or TDLN; or a combination of these possibilities, whereby activation of tumor-resident T cells accelerates recruitment of peripheral T cells to the TME through chemokine secretion or cDC activation. Given that most T cell proliferation in the peripheral blood occurs within 1 week of anti–PD-1 therapy and is largely diminished by 3 weeks (7, 11), what is the timing of clonal replacement? Does clonal T cell recruitment and expansion within the tumor follow the same kinetics? Chemical inhibition of T cell migration can abrogate tumor regression following ICB in some mouse models, but these results vary according to dosage and timing, indicating that such factors can influence therapeutic outcomes (4, 15).

Another area of active investigation concerns how peripheral T cell dynamics are influenced by tumor-intrinsic factors, such as tumor site and mutational heterogeneity. Skin and lung cancers have been most extensively profiled and have high amounts of immune infiltration. Comparisons between metastatic sites suggested that tumors in more immunosuppressive tissue microenvironments (such as the liver) are the least responsive to PD-1 blockade, but how tumor location influences T cell dynamics during therapy remains unclear (8). Because clonal neoantigen burden is also associated with clinical response to ICB, and TILs reactive to clonal neoantigens are present prior to treatment (1), how do clonal antigens escape immune surveillance before ICB, and what is the relationship between tumor evolution and T cell dynamics? Distinguishing general immunological effects of PD-1 blockade from antitumor immune responses will require studies pairing TIL clonotypes to their target antigens to determine how T cell phenotypes and clonal dynamics are influenced by antigen specificity.

Thus, it is possible that preexisting TILs represent a correlate, rather than a cause, of clinical responses in immune-infiltrated tumors. Namely, intratumoral immune infiltration may simply reflect TME properties such as mutational load, immunogenicity, and/or tumor site that promote continued surveillance by tumor-extrinsic T cells. Future investigations into the origins and mechanisms of response to ICB should help to identify prognostic factors underlying clinical efficacy and will facilitate the rational design of effective treatment combinations to improve responses. In particular, the combination of ICB with immune-modulating agents that amplify peripheral T cell recruitment, such as immunostimulatory agonist antibodies and cytokine-based immunotherapies, may expand the utility of ICB to a wider patient population.

Acknowledgments: A.T.S. is a scientific founder of Immunai. H.Y.C. is a cofounder of Accent Therapeutics, Boundless Bio and an adviser to 10x Genomics, Arsenal Biosciences, and Spring Discovery.

Immunotherapy for Kidney Cancer: Stage 4 and More

Immunotherapy for Kidney Cancer: Stage 4 and More

  • March 25, 2021

  • Immunotherapy is used in treating kidney cancer to help your immune system fight off abnormal cells.
  • The main types of immunotherapy for kidney cancer include immune checkpoint inhibitors and cytokines.
  • While used in treating advanced kidney cancer, there is a high risk for side effects which should be discussed with your doctor.

Immunotherapy is a process where certain medications are used to boost your immune system to increase its ability to fight off abnormal cells. This type of treatment has been used in cancer therapies, including those that help treat kidney cancer.

Depending on your situation, your doctor may recommend immunotherapy as either a first-line or second-line treatment.

However, it’s also important to know that some of these therapies pose serious side effects, and their effectiveness may be limited in advanced forms of kidney cancer.

Read on to learn more about the types of immunotherapy available for kidney cancer and how effective they may be.

The main types of immunotherapy used specifically for kidney cancer include:

  • immune checkpoint inhibitors, such as CTLA-4, PD-1, and PD-L1 inhibitors
  • cytokines, such as interleukin-2 and interferon-alfa

Learn more about each type and the possible side effects of each below.

CTLA-4 inhibitors

CTLA-4 inhibitors belong to a group of immunotherapy treatments called immune checkpoint inhibitors.

Checkpoints are types of proteins on cells that help deliver immune responses. Immune checkpoint inhibitors ensure that all checkpoints are working to protect healthy cells against cancerous ones.

Your doctor may recommend CTLA-4 inhibitors to help block proteins of the same name. These usually develop on T-cells.

Ipilimumab (brand name Yervoy) is a CTLA-4 inhibitor used for kidney cancer.

It may be used as a combination treatment with other immune checkpoint inhibitors. This therapy is delivered via intravenous (IV) infusions for up to four times total, with 3 weeks in between treatments.

Side effects from CTLA-4 inhibitors may include:

  • fatigue
  • skin rashes
  • itchy skin
  • diarrhea

PD-1 inhibitors

PD-1 is another type of immune checkpoint inhibitor that also targets T-cells.

Two options include nivolumab (Opdivo) and pembrolizumab (Keytruda), which are both delivered via IV spaced weeks apart.

PD-1 may help slow the growth of kidney cancer cells and expose tumor cells to immune system targeting and death, which may decrease tumor size.

Side effects may include:

  • fatigue
  • loss of appetite
  • constipation or diarrhea
  • nausea
  • itchy skin or rash
  • joint pain
  • coughing
  • anemia
  • liver abnormalities

PD-L1 inhibitors

PD-L1 is a protein found in some cancer cells. By blocking this protein with PD-L1 inhibitors, the immune system may help shrink or stop further cancerous growths.

Avelumab (Bavencio) is a type of PD-L1 inhibitor used for kidney cancer that’s also delivered though IV treatments. This medication is administered every 2 weeks and may be combined with other medications.

Possible side effects include:

  • fatigue
  • abdominal pain
  • diarrhea
  • high blood pressure (hypertension)
  • breathing difficulties
  • skin blisters or rashes
  • musculoskeletal pain

Interleukin-2 (IL-2) cytokines

IL-2 is a high-dose cancer treatment that’s administered via IV. Due to a high risk of side effects, it’s typically only used in advanced kidney cancer that hasn’t responded to other types of immunotherapy.

Aldesleukin (Proleukin) is an example of a cytokine that targets the IL-2/IL-2R pathway.

IL-2 is just one class of cytokines sometimes used to treat kidney cancer. Cytokines are types of proteins that may help boost the immune system, possibly shrinking or killing cancer cells and decreasing tumor size.

Your doctor will consider whether you are in good enough health to tolerate the side effects. Such effects may include:

  • kidney damage
  • low blood pressure (hypotension)
  • rapid heart rate
  • heart attack
  • intestinal bleeding
  • gastrointestinal concerns
  • breathing difficulties
  • mental changes
  • high fever, sometimes accompanied by chills
  • fluid buildup in the lungs
  • extreme fatigue

Interferon-alfa cytokines

Interferon-alfa is another type of cytokine treatment that may be an alternative to IL-2. The downside is that this treatment may not be effective in treating kidney cancer alone.

In fact, your doctor may use it as part of a combination drug, which is injected under your skin three times per week.

Side effects from interferon-alfa treatment may include:

  • fatigue
  • fever and chills
  • nausea
  • muscle aches

Stages 1, 2, and 3 are considered early forms of kidney cancer. Most of these cases may be treated with surgery.

If you have stage 4, or more advanced kidney cancer, your doctor may recommend immunotherapy. This type of treatment is also used in recurrent cancers.

While the aforementioned immunotherapies may be used for stage 4 kidney cancer, there are some limitations and combination therapies that may be considered. These include:

  • IL-2 cytokines, which are only typically used if your doctor determines the possible benefits outweigh the high risk of side effects
  • PD-L1 inhibitor combination therapies, specifically avelumab and a targeted therapy called axitinib (Inlyta)
  • PD-1 inhibitor combination therapies, such as nivolumab used with another type of targeted therapy called cabozantinib (Cabometyx)

Overall, researchers believe that immune checkpoint inhibitors —particularly PD-1 — may be helpful for advanced clear cell renal cell carcinoma (ccRCC).

However, these inhibitors may produce the opposite effect in advanced kidney cancer.

There are many different types of immunotherapy, so it’s difficult to give an estimate of the overall success rates for treatment. However, research has helped to reveal some trends that may improve treatment outlook.

For example, combination therapies that use immunotherapy with a targeted therapy are thought to be more successful in treating advanced kidney cancer than using each treatment individually.

Several studies have demonstrated that combining treatments can improve progression-free survival, the amount of time that patients go without their disease worsening.

Many of these trials compare combination immunotherapy treatments to targeted therapy with a tyrosine kinase inhibitor (TKI) medication called sunitinib (Sutent), which discourages tumor growth.

Sunitinib has been used as a first-line therapy for advanced kidney cancer since 2006.

For example, a 2018 study found that combining nivolumab and ipilimumab led to a 75 percent survival rate at 18 months, compared with a 60 percent rate when using sunitinib alone.

Of the 1,096 patients, the median progression-free survival was 11.6 months with the combination and 8.4 months with sunitinib.

A 2019 study, funded by Pfizer, paired avelumab plus axitinib in comparison with sunitinib.

Among the 866 patients, the median progression-free survival was 13.8 months with the combination therapy, as compared with 8.4 months with the single treatment.

Another 2019 study, funded by Merck, combined pembrolizumab and axitinib in comparison with sunitinib.

Among the 861 patients, the median progression-free survival was 15.1 months in the pembrolizumab/axitinib group and 11.1 months in the sunitinib group.

IL-2 and interferon-alfa cytokines are thought to possibly shrink kidney cancer cells in only a small percentage of people. As such, cytokine treatment is reserved for cases where other immunotherapies don’t work.

Due to the way they modify your immune system’s responses, checkpoint inhibitors may sometimes send your immune system into overdrive, leading to organ damage. Possible affected areas may include the:

  • liver
  • lungs
  • kidneys
  • intestines
  • thyroid gland

To minimize side effects in these areas of the body, your doctor may prescribe oral corticosteroids.

These immunosuppressants are sometimes used in place of traditional immunotherapy for kidney cancer if you don’t respond well to these types of therapies.

Report any new side effects from immunotherapy to your doctor right away. You may also consider talking with them about complementary medical approaches to help manage existing side effects, such as:

  • biofeedback
  • meditation and yoga
  • acupuncture
  • massage or reflexology
  • herbs, vitamins, or botanicals
  • diets

Research in the areas of kidney cancer development, diagnosis, and treatment are ongoing.

Recent clinical trials have also looked at the efficacy of immunotherapies for kidney cancer, along with the combinations with targeted drugs such as axitinib and cabozantinib.

Once the safety of new treatments has been tested in a clinical setting, the FDA may approve future kidney cancer therapies.

You may also consider talking with your doctor about the possibility of participating in clinical trials. The National Cancer Institute’s current list of clinical trials for kidney cancer treatment may be found here.

Immunotherapy may treat kidney cancer by changing the way your immune system responds to cancerous cells. These come in the form of immune checkpoint inhibitors or cytokines.

Sometimes, immunotherapy may be combined with targeted therapies for better outcomes in advanced cancer.

Talk with your doctor about immunotherapy as a possible kidney cancer treatment option. You’ll also want to ask about the risk for side effects and complications.

New therapy extends breast cancer survival rate, prevents reoccurrence

New cancer immunotherapy recruits help from lymphatic vessels

  • March 24, 2021

CHICAGO — Immunotherapy, which recruits the body’s own immune system to attack cancer, has given many cancer patients a new avenue to treat the disease.

But many cancer immunotherapy treatments can be expensive, have devastating side effects, and only work in a fraction of patients.

Researchers at the Pritzker School of Molecular Engineering at the University of Chicago have developed a new therapeutic vaccine that uses a patient’s own tumor cells to train their immune system to find and kill cancer.

The vaccine, which is injected into the skin just like a traditional vaccine, stopped melanoma tumor growth in mouse models. It even worked long-term, destroying new tumors long after the therapy was given.

The results were published March 24 in the journal Science Advances.

“This is a new strategy for immunotherapy,” said Prof. Melody Swartz, who led the research. “It has the potential to be more efficacious, less expensive and much safer than many other immunotherapies. It is truly personalized medicine that has the potential to overcome many issues that arise with other treatments.”

Recruiting a broad immune response

In many ways, the vaccine works like a traditional flu vaccine: it uses a less-potent version of the pathogen (here, a patient’s own cancer cells, which are lethally irradiated before injection) to train the immune system to fight the disease.

However, rather than a preventive measure, this is a therapeutic vaccine, meaning it activates the immune system to destroy cancer cells anywhere in the body. To create it, Swartz and her team used melanoma cells from mice and then engineered them to secrete vascular endothelial growth factor C (VEGF-C).

VEGF-C causes tumors to strongly associate with the body’s lymphatic system, which is normally considered bad for the patient, since it can promote metastasis. But the team recently found that when tumors activate surrounding lymphatic vessels, they are much more responsive to immunotherapy and promote “bystander” T cell activation, leading to a more robust and long-lasting immune response.

The team then had to figure out how to harness the benefits of lymphatic activation in a therapeutic strategy while avoiding the potential risks of metastasis.

‘Training’ the immune system

Maria Stella Sasso, a postdoctoral fellow and first author of the paper, tested many different strategies before settling on the vaccine approach, which allowed immune “training” in a site distant from the actual tumor.

The strategy of using a patient’s own irradiated tumor cells in a therapeutic vaccine had previously been established by Glenn Dranoff and colleagues at the Novartis Institutes for BioMedical Research, who developed GVAX, a cancer vaccine that has been shown safe in clinical trials. Sasso decided to try this approach with VEGF-C rather than the cytokine used in GVAX. She dubbed the strategy “VEGFC-vax.”

After engineering the cells to express VEGF-C, the research team irradiated them, so they would die within a few weeks. When they injected the cells back into the skin of mice, they found that the dying tumor cells could attract and activate the immune cells, which then could recognize and kill the actual tumor cells growing on the opposite side of the mouse. Since each tumor has its own unique signature of hundreds of molecules that the immune system can recognize, the vaccine promoted a broad, robust immune response.

That led to the prevention of tumor growth in all of the mice. It also led to immunological memory, preventing new tumor growth when tumor cells were re-introduced 10 months later.

“This shows that the therapy may provide long-term efficacy against metastasis and relapse,” said Swartz, William B. Ogden Professor of Molecular Engineering.

Potential therapy for many types of cancers

Conceptually, this is the first strategy to exploit the benefits of local lymphatic vessel activation for more robust and specific immune response against tumor cells.

Unlike immunotherapeutic strategies that stimulate the immune system in a general way, such as checkpoint blockade or the many cytokines currently in preclinical development, this new immunotherapy activates only tumor-specific immune cells. Theoretically, this would avoid common side effects of immune stimulants, including immunotoxicity and even death.

And while many other cancer immunotherapies, such as CAR-T cell therapy, are tumor-specific, these strategies only work against tumor cells that express specific pre-identified tumor markers called antigens. Cancer cells can eventually overcome such treatments by shedding these markers or mutating, for example.

VEGFC-vax, however, can train immune cells to recognize a large number and variety of tumor-specific antigens. More importantly, these antigens do not need to be identified ahead of time.

The researchers are working to test this strategy on breast and colon cancers and think it could theoretically work on any type of cancer. They hope to ultimately take this therapy to clinical trials.

“We think this has huge promise for the future of personalized cancer immunotherapy,” Swartz said.

###

Citation: “Lymphangiogenesis-inducing vaccines elicit potent and long-lasting T cell immunity against melanomas,” Sasso et. al, Science Advances, Mar. 24

Funding: National Cancer Institute R01 CA219304

The University of Chicago is a leading academic and research institution that has driven new ways of thinking since its founding in 1890. As an intellectual destination, the University draws scholars and students from around the world to its campuses and centers around the globe. The University provides a distinctive educational experience and research environment, empowering individuals to challenge conventional thinking and pursue field-defining research that produces new understanding and breakthroughs with global impact.

Deactivating gene could boost immunotherapy for head and neck cancer

Deactivating gene could boost immunotherapy for head and neck cancer

  • March 24, 2021

Inhibiting the KDM4A enzyme slowed the growth of head and neck cancer in mouse models, also demonstrating promise to aid immunotherapy.


By targeting an enzyme that plays a key role in head and neck cancer cells, researchers were able to significantly slow the growth and spread of tumours in mice and enhance the effectiveness of an immunotherapy to which these types of cancers often become resistant. The study was conducted at the University of California, Los Angeles (UCLA) School of Dentistry, US. 

According to the team, these findings could help researchers develop more refined approaches to combatting highly invasive head and neck squamous cell cancers, which primarily affect the mouth, nose and throat.

The research team demonstrated that by targeting a vulnerability in the cellular process of tumour duplication and immunity, they could affect tumour cells’ response to immunotherapy.

The enzyme they focused on, KDM4A, is an epigenetic factor – a molecule that regulates gene expression, silencing some genes in cells and activating others. In squamous cell head and neck cancers, overexpression of KDM4A promotes gene expression associated with cancer cell replication and spread.

The team say that tumour cells can spread undetected by the immune system and without surveillance can metastasise to lymph nodes or other parts of the body. In this instance, tumour cells that develop in the epithelial layer that lines the structures of the head and neck can turn into head and neck squamous cell carcinoma. 

The researchers wondered what would happen if the signalling pathways for cancer replication were disrupted. 

“We know that the KDM4A gene plays a critical role in cancer cell replication and spread, so we focused our study on removing this gene to see if we would get an opposite response,” said Professor Cun-Yu Wang, the study’s corresponding author. 

By removing the KDM4A gene in mouse models, the researchers witnessed a notable decrease in squamous cell carcinomas and far less metastasis of cancer to the lymph nodes – a precursor to the spread of the disease throughout the body. They also discovered that the KDM4A’s removal also led to the recruitment and activation of the body’s infection-fighting T cells, which killed cancer cells and stimulated inherent tumour immunity.

They then sought to uncover why the squamous carcinoma cells had such a poor response to immunotherapy treatment. In another set of mouse models, they again removed KDM4A and introduced a PD-1 blockade, which signals immunotherapy drugs to attack cancer cells. The combination of immunotherapy and KDM4A removal further decreased squamous cell cancer growth and lymph node metastasis.

Next, the researchers tested whether a small-molecule inhibitor of KDM4A could improve the efficacy of the original PD-1 blockade-based immunotherapy. They found that the inhibitor also significantly helped remove cancer stem cells, which are associated with cancer relapse.

The team say their findings hold promise for the development of more specific inhibitors for KDM4A and more effective cancer immunotherapies.

The findings are published in Molecular Cell.

New therapy extends breast cancer survival rate, prevents reoccurrence

Deactivating cancer cell gene boosts immunotherapy for head and neck cancers

  • March 24, 2021

By targeting an enzyme that plays a key role in head and neck cancer cells, researchers from the UCLA School of Dentistry were able to significantly slow the growth and spread of tumors in mice and enhance the effectiveness of an immunotherapy to which these types of cancers often become resistant.

Their findings, published online in the journal Molecular Cell, could help researchers develop more refined approaches to combatting highly invasive head and neck squamous cell cancers, which primarily affect the mouth, nose and throat.

Immunotherapy, which is used as a clinical treatment for various cancers, harnesses the body’s natural defenses to combat disease. Yet some cancers, including head and neck squamous cell carcinomas, don’t respond as well to the therapy as others do. The prognosis for these head and neck cancers is poor, with a high five-year mortality rate, and there is an urgent need for effective treatments.

The UCLA research team, led by distinguished professor Dr. Cun-Yu Wang, chair of oral biology at the dentistry school, demonstrated that by targeting a vulnerability in the cellular process of tumor duplication and immunity, they could affect tumor cells’ response to immunotherapy.

The enzyme they focused on, KDM4A, is what is known as an epigenetic factor — a molecule that regulates gene expression, silencing some genes in cells and activating others. In squamous cell head and neck cancers, overexpression of KDM4A promotes gene expression associated with cancer cell replication and spread.

It is well known that tumor cells can spread undetected by the immune system and, without surveillance, can metastasize to lymph nodes or other parts of the body. In this instance, tumor cells that develop in the epithelial layer that lines the structures of the head and neck can turn into head and neck squamous cell carcinoma when unchecked.

Cancer cell replication occurs through the abnormal spread and activation of signaling pathways for cancer cells, and the researchers asked the question: If we can disrupt these processes and identify a vulnerability, can we change the body’s response to fighting cancer cells and its response to outside immunotherapy?

“We know that the KDM4A gene plays a critical role in cancer cell replication and spread, so we focused our study on removing this gene to see if we would get an opposite response,” said Wang, the study’s corresponding author and a member of the UCLA Jonsson Comprehensive Cancer Center.

By removing the KDM4A gene in their mouse models, the researchers witnessed a notable decrease in squamous cell carcinomas and far less metastasis of cancer to the lymph nodes — a precursor to the spread of the disease throughout the body. Surprisingly, they also discovered that the KDM4A’s removal also led to the recruitment and activation of the body’s infection-fighting T cells, which killed cancer cells and stimulated inherent tumor immunity.

They then sought to uncover why the squamous carcinoma cells had such a poor response to immunotherapy treatment. In another set of mouse models, they again removed KDM4A and introduced a PD-1 blockade, which signals immunotherapy drugs to attack cancer cells. The combination of immunotherapy and KDM4A removal further decreased squamous cell cancer growth and lymph node metastasis.

Next, the researchers tested whether a small-molecule inhibitor of KDM4A could improve the efficacy of the original PD-1 blockade-based immunotherapy. They found that the inhibitor also significantly helped remove cancer stem cells, which are associated with cancer relapse.

The findings hold promise for the development of more specific inhibitors for KDM4A and more effective cancer immunotherapies.

“I am continuously impressed by Dr. Cun-Yu Wang and his team for breaking through barriers in our understanding of cancer-causing cellular processes,” said Dr. Paul Krebsbach, dean and professor at the UCLA School of Dentistry. “The results of this study have major implications for the development of more effective, life-saving cancer therapies.”

###

The work was supported by grants from the National Institute of Dental and Craniofacial Research, which is part of the National Institutes of Health.

Dr. Wang is the Dr. No-Hee Park Professor of Dentistry at UCLA, a professor at the UCLA Samueli School of Engineering and a member of Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

Additional authors include Wuchang Zhang, Wei Liu, Lingfei Jia, Demeng Chen and Dr. Insoon Chang, all of the Laboratory of Molecular Signaling at the UCLA School of Dentistry and members of the Jonsson Comprehensive Cancer Center, and Dr. Michael Lake and Laurent Bentolila, both of the California NanoSystems Institute at UCLA.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

Bacteria residing within tumor cells can boost cancer immunotherapy

Bacteria residing within tumor cells can boost cancer immunotherapy

  • March 22, 2021

Cancer immunotherapy may get a boost from an unexpected direction: bacteria residing within tumor cells. In a new study published in Nature, researchers at the Weizmann Institute of Science and their collaborators have discovered that the immune system “sees” these bacteria and shown they can be harnessed to provoke an immune reaction against the tumor.

The study may also help clarify the connection between immunotherapy and the gut microbiome, explaining the findings of previous research that the microbiome affects the success of immunotherapy.

Immunotherapy treatments of the past decade or so have dramatically improved recovery rates from certain cancers, particularly malignant melanoma; but in melanoma, they still work in only about 40% of the cases.

Prof. Yardena Samuels of Weizmann’s Molecular Cell Biology Department studies molecular “signposts” – protein fragments, or peptides, on the cell surface – that mark cancer cells as foreign and may therefore serve as potential added targets for immunotherapy. In the new study, she and colleagues extended their search for new cancer signposts to those bacteria known to colonize tumors.

Using methods developed by departmental colleague Dr. Ravid Straussman, who was one of the first to reveal the nature of the bacterial “guests” in cancer cells, Samuels and her team, led by Dr. Shelly Kalaora and Adi Nagler (joint co-first authors), analyzed tissue samples from 17 metastatic melanoma tumors derived from nine patients. They obtained bacterial genomic profiles of these tumors and then applied an approach known as HLA-peptidomics to identify tumor peptides that can be recognized by the immune system.

The research was conducted in collaboration with Dr. Jennifer A. Wargo of the University of Texas MD Anderson Cancer Center, Houston, Texas; Prof Scott N. Peterson of Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California; Prof Eytan Ruppin of the National Cancer Institute, USA; Prof Arie Admon of the Technion – Israel Institute of Technology and other scientists.

The HLA peptidomics analysis revealed nearly 300 peptides from 41 different bacteria on the surface of the melanoma cells. The crucial new finding was that the peptides were displayed on the cancer cell surfaces by HLA protein complexes – complexes that are present on the membranes of all cells in our body and play a role in regulating the immune response.

One of the HLA’s jobs is to sound an alarm about anything that’s foreign by “presenting” foreign peptides to the immune system so that immune T cells can “see” them. “Using HLA peptidomics, we were able to reveal the HLA-presented peptides of the tumor in an unbiased manner,” Kalaora says. “This method has already enabled us in the past to identify tumor antigens that have shown promising results in clinical trials.”

It’s unclear why cancer cells should perform a seemingly suicidal act of this sort: presenting bacterial peptides to the immune system, which can respond by destroying these cells. But whatever the reason, the fact that malignant cells do display these peptides in such a manner reveals an entirely new type of interaction between the immune system and the tumor.

This revelation supplies a potential explanation for how the gut microbiome affects immunotherapy. Some of the bacteria the team identified were known gut microbes. The presentation of the bacterial peptides on the surface of tumor cells is likely to play a role in the immune response, and future studies may establish which bacterial peptides enhance that immune response, enabling physicians to predict the success of immunotherapy and to tailor a personalized treatment accordingly.

Moreover, the fact that bacterial peptides on tumor cells are visible to the immune system can be exploited for enhancing immunotherapy. “Many of these peptides were shared by different metastases from the same patient or by tumors from different patients, which suggests that they have a therapeutic potential and a potent ability to produce immune activation,” Nagler says.

In a series of continuing experiments, Samuels and colleagues incubated T cells from melanoma patients in a laboratory dish together with bacterial peptides derived from tumor cells of the same patient. The result: T cells were activated specifically toward the bacterial peptides.

Our findings suggest that bacterial peptides presented on tumor cells can serve as potential targets for immunotherapy. They may be exploited to help immune T cells recognize the tumor with greater precision, so that these cells can mount a better attack against the cancer. This approach can in the future be used in combination with existing immunotherapy drugs.”


Yardena Samuels, Professor, Molecular Cell Biology Department, Weizmann Institute of Science

Immunotherapy vs Chemotherapy: Uses, Similarities & Differences

Immunotherapy vs Chemotherapy: Uses, Similarities & Differences

  • March 18, 2021

Immunotherapy and chemotherapy are two commonly used cancer treatments. Both types of therapy involve the use of drugs to stop the growth of cancer cells. Although they have the same goal, the way they accomplish it is different.

  • Immunotherapy enhances your immune system’s ability to target cancer cells.
  • Chemotherapy acts directly on cancer cells to keep them from replicating.

Your healthcare team may recommend both treatments at the same time or in addition to other cancer treatments such as radiation therapy or surgery.

Keep reading as we examine the similarities and differences of immunotherapy versus chemotherapy.

Cancer cells are abnormal cells that replicate uncontrollably. Normally, your immune system destroys abnormal cells, but many types of cancer cells are able to hide from your immune system.

Cancer cells may be able to hide from your immune system by:

  • having genetic changes that reduce their visibility
  • containing proteins that turn off your immune cells
  • changing cells around the tumor so that they interfere with your immune response.

Immunotherapy helps your immune system recognize and destroy cancer cells

Immunotherapy drugs help your immune system recognize cancer and destroy it. The ultimate goal of immunotherapy is to create a group of T cells that specifically target cancer. T cells are a special type of white blood cell that attacks foreign invaders.

Immunotherapy is a growing area of research. Many scientists are optimistic it could lead to breakthroughs in cancer treatment.

How immunotherapy drugs are delivered

You can take immune therapy drugs through an IV, capsules, or creams. Immunotherapy is used to treat a wide range of cancers but isn’t yet as widely used as chemotherapy, radiation therapy, and surgery.

Types of immunotherapy drugs

Immunotherapy drugs can be divided into several categories depending on how they specifically target your immune system.

  • Immune checkpoint inhibitors. These drugs block immune checkpoints. Immune checkpoints are part of your natural immune response that keeps your immune system from being too aggressive.
  • T-cell transfer therapy. This type of treatment enhances the ability of your T cells to recognize and attack cancer cells.
  • Monoclonal antibodies. Monoclonal antibodies are proteins that bind to cancer cells and mark them for your immune system.
  • Treatment vaccines. Treatment vaccines help boost your immune system’s response to cancer cells.
  • Immune system modulators. Immune system modulators either generally enhance your immune system or enhance a specific part of your immune system.

Chemotherapy is a chemical drug therapy that helps keep cancer cells from replicating. The first chemotherapy drugs were developed around the 1940s.

Chemotherapy helps stop cancer cells from replicating

Chemotherapy helps treat cancer by:

  • decreasing the number of cancer cells in your body
  • reducing the chances of the cancer spreading or returning
  • shrinking tumors
  • reducing your symptoms

How chemotherapy is delivered

Chemotherapy drugs can be administered in a number of ways, such as:

  • orally
  • through an IV
  • through injections
  • into the fluid between your brain and spinal cord
  • directly into an artery
  • directly into your abdominal cavity
  • topically

Chemotherapy is used to target a wide range of types of cancers. However, the chemicals in chemotherapy drugs can also damage healthy cells, which leads to common side effects like hair loss and nausea.

Types of chemotherapy drugs

There are at least 150 chemotherapy drugs that can be used for treating cancer. The type of drug your doctor will use depends on such factors as:

  • your age and health
  • the type of cancer you have
  • how far it’s progressed
  • if you’ve previously received chemotherapy treatment

Each category of chemotherapy drug has its own mode of action, and some drugs work better for certain cancers. This article discusses the different categories of chemotherapy drugs and which types of cancers they’re typically used for.

Chemotherapy and immunotherapy are similar in many ways. Both are drug therapies that seek to destroy cancer cells and can be used to treat many different types of cancers.

Although they have a similar goal, the way these treatments destroy cancer cells differs. Immunotherapy seeks to enhance your immune system’s ability to kill cancer cells. Chemotherapy drugs directly impair a cancer cell’s ability to replicate.

Length of action

Chemotherapy stops working once the drugs are no longer administered. Immunotherapy can potentially stimulate your immune system to continue fighting cancer even after treatment has stopped.

When you first start treatment, chemotherapy has the potential to have an almost immediate effect on shrinking a tumor. Immunotherapy often takes longer to take effect.

Side effects

Both types of treatment can potentially cause mild and serious side effects.

Chemotherapy targets cells that rapidly divide, such as cancer cells, but it can also damage other cells in your body that rapidly divide such as hair, skin, blood, and intestinal cells.

Damage to these cells can lead to many potential side effects such as nausea, hair loss, and mouth sores. The most common side effect of chemotherapy is fatigue.

Many immunotherapy side effects come from overactivation of your immune system. Mild side effects can include nausea, flu-like symptoms, or a reaction at the injection site. In more serious cases, it can cause your immune system to attack your organs.

Cost

The cost of chemotherapy and immunotherapy can vary widely based on factors such as how long you need treatment, what type of cancer you have, and how far your cancer has spread.

A 2020 study published in the Journal of Clinical Oncology sought to compare the average cost of checkpoint inhibitors — which is a type of immunotherapy — versus chemotherapy in patients dealing with lung cancer.

The researchers found the average cost of immunotherapy in 2015 was $228,504 versus $140,970 for chemotherapy. In 2016, the average cost was $202,202 for immunotherapy and $147,801 for chemotherapy.

Immunotherapy and chemotherapy both have the potential to be effective cancer treatments. One isn’t necessarily better than the other. The one that works best for treating your cancer depends on many factors such as where your cancer is and how far it has progressed.

Discuss with your doctor the best treatment option for your particular situation. Your doctor can explain the advantages and disadvantages of each treatment and explain how to best integrate them in a holistic treatment plan.

Chemotherapy and immunotherapy are two types of drug therapies used to treat cancer. The goal of immunotherapy is to boost the function of your immune system so that it can destroy cancer cells. Chemotherapy directly inhibits the ability of cancer cells to replicate themselves.

Both types of treatment can be effective at treating cancer. They may be used together or combined with other cancer treatments. Discuss treatment options with your doctor to learn the best options for your situation.

Study: What level of neutralising antibody protects from COVID-19? Image Credit: Juan Gaertner / Shutterstock

What is a protective neutralizing antibody titer against SARS-CoV-2 infection?

  • March 15, 2021

Caused by the worldwide spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus disease 2019 (COVID-19) pandemic continues to damage global public health and economic vitality. The only hope of returning to any semblance of normalcy lies with the achievement of population immunity, either by natural infection or by vaccination.

A new preprint, released on the medRxiv* server, describes a predictive model of protective immunity against SARS-CoV-2 infection that could help evolve optimal vaccination strategies to maintain protection and reduce the death rate.

Study: What level of neutralising antibody protects from COVID-19? Image Credit: Juan Gaertner / Shutterstock

As natural infection is associated with a frighteningly high loss of life (over 2.6 million deaths and counting), vaccine-elicited immunity is the only viable way out. Active immunity has been observed to set in following the vast majority of infections.

Researchers estimate that convalescents with antibodies against the virus (seropositive convalescents) are protected against reinfection by 90%, while vaccine antibodies do the job of reducing reinfection by 50-85%. The duration for which protective immunity lasts is unknown, but the immune response is known to wane rapidly.

Also, new variants have rapidly emerged that could be resistant to antibodies specific to the antigens of the older strains.

The current study aims to identify the factors that predict adequate protection against SARS-CoV-2 infection so that it becomes possible to predict how the changes in immunity levels will affect the clinical outcomes of the individual patient. This would help to tailor vaccination and immunotherapy protocols so as to ensure this level of immunity is created and maintained – and, in turn, this would help economic activity to begin again with confidence.

In early influenza pandemics, a hemagglutination inhibition (HAI) titer of 1:40 is correlated with 50% protection from infection. This level results from analyzing data on standardized HAI tests carried out on serum from individuals challenged with the influenza virus vs controls.

The lack of similar assays for immunity to SARS-CoV-2 has made it difficult to compare the level of immunity in a susceptible population to that in a resistant one, and human challenge models are impossible with the current death rate.

Immunological mechanisms associated with protection from infection include neutralizing antibodies, as well as memory T and B cells. The use of convalescent serum and therapeutic antibodies (such as the Regeneron cocktail) has proved the major role played by neutralizing antibodies.

The current study used neutralization titers obtained during in vitro studies with sera from vaccinated and convalescent individuals. The neutralization capacity of standardized convalescent serum has been suggested to be more comparable to the results from a variety of assays, and so the sera were normalized against this standard.

Neutralization titers were averaged, and the log standard deviation was also determined in each study for the sake of achieving comparable values. The normalized mean convalescent neutralizing titer was calculated for the same assay in the same study, and values from different studies were compared against the reported phase 3 vaccine efficacy.

The authors thus obtained a strong linear relationship between the mean neutralization level and the protective efficacy for different vaccines. The results show that a 50% protective neutralization level is achieved at about a fifth of the antibody titer found in convalescent plasma, on average.

That is, the level of neutralizing antibodies required to protect against 50% of infection is one-fifth of the mean neutralizing antibody titer found in convalescent serum. Again, when adjusted to prevent false results due to a normal distribution of data, they found that the estimated protective level was about 29% of the mean convalescent level, slightly higher than the earlier estimation. However, the latter figure represents the titer needed to ensure 100% protection.

This demonstrates the ability to predict the correlation between the average level of protection and the observed efficacy of protection if the level of neutralization titers and their distribution is known.

To test the utility of this approach in arriving at the protective efficacy of a new vaccine, the researchers analyzed the data against all possible groups of vaccinated or convalescent subjects, apart from one, to predict the efficacy of the last group.

They tested the predictive accuracy against a new vaccine with phase 3 efficacy results recently released, at around 81%. The researchers found that, with the mean observed neutralization level of around 79% of the convalescent titer measured in that study, the new vaccine had a predicted efficacy of around 79%, which is close to the reported figure.

This study can be carried forward with access to more standardized assay and trial results, which would yield more homogeneous data. The researchers caution that the association of neutralization with protective efficacy in these studies does not imply that such antibodies mediate protection against infection.

Instead, other immune responses leading to protection could be correlated with neutralizing titer, and thus create an apparent association. Thus, examining the predictive value of other serological and cellular immune markers is necessary to identify the best predictive marker, compared to neutralization.

Nonetheless, the rapid decline of neutralization titers after natural infection and vaccination has been observed. The mean neutralization titer wanes by half over the first eight months following infection. However, the decline likely slows down over time.

The researchers compared the neutralization titer decay in convalescent sera and in vaccine recipient sera. They found that when measured at 26-115 days from vaccination or from the onset of symptoms, the titers appeared to decline at almost the same rate.

The researchers assumed that neutralization is the major mechanism of protection against infection or at least the major correlate; that both vaccine-induced and natural antibodies decay at the same rate; and that the rate of decay is unrelated to the initial titer. The researchers then constructed a model of neutralization and protection over the first 250 days after vaccination, using the half-life of the 90-day neutralization titer from convalescent sera.

This showed that decreasing neutralization titers affect protection from infection in a non-linear fashion, with the drop being proportional to the initial vaccine efficacy.

For example, a vaccine starting with an initial efficacy of 95% would be expected to maintain 58% efficacy by 250 days. However, a response starting with an initial efficacy of 70% would be predicted to drop to 18% efficacy after 250 days.”

This approach would also allow an estimation of the time taken for the initial efficacy to drop to 50% or 70%, thus helping to determine the interval necessary before a boost will be needed to maintain minimal neutralization efficacy levels.

The model also shows that a lower neutralization titer against a variant of concern (VOC) will have a greater impact on vaccines with lower protective titers against the wildtype virus. If the vaccine has high efficacy (95%) against the latter, for instance, a five-fold drop in efficacy would reduce the efficacy against the VOC to 67%.

Conversely, if the vaccine has only 70% efficacy at first, the efficacy against the VOC at five-fold lower levels will be only 25%. Such figures are of concern in the light of recent research, which shows that the neutralization titer against the South African VOC B.1.351 is 7.6-9-fold lower than for the earlier variants.

Protection from severe infection.

Protection from severe infection. (A) The predicted relationship between efficacy against mild (any) SARS-CoV-2 infection (x-axis) versus efficacy against severe infection (y-axis). The black line indicates the best fit model for the relationship between protection against any versus severe SARS-CoV-2 infection. Shaded areas indicate 95% confidence intervals. Efficacy against severe infection was calculated by using a severe threshold that was a factor of 0.16 smaller than mild infection (CI = 0.039 to 0.66). (B) Extrapolating the decay of neutralisation titres over time. This model assumes a half-life of SARS-CoV-2 neutralisation titre of 90 days over the first 250 days 5, after which the decay decreases (at rate 0.01d-1) until a 10-year half-life is achieved 33,34. For different initial starting levels the model projects the decay in level over the subsequent 1000 days. The green line indicates the predicted 50% protective titre from mild SARS-CoV-2 infection, and the purple line indicates the 50% protective titre from severe SARS-CoV-2 infection. The model illustrates that, depending on the initial neutralisation level, individuals may maintain protection from severe infection whilst becoming susceptible to mild infection (ie: with neutralisation levels remaining in the green shaded region). (C) Extrapolating the trajectory of protection for groups with different starting levels of protection. The model uses the same assumptions on the rate of immune decay discussed in panel B. Note: The projections beyond 250 days rely on an assumption of how the decay in SARS-CoV-2 neutralisation titre will slow over time. In addition, the modelling only projects how decay in neutralisation is predicted to affect protection. Other mechanisms of immune protection may play important roles in providing long-term protection that are not captured in this simulation.

The study also shows that the 50% neutralization level that confers protection against severe infection was 3% of the average convalescent level, assuming that neutralization and not cellular responses are important in this protection.

This six-fold difference in the protective titer against severe infection relative to that against any infection will probably be reflected at all levels of vaccine efficacy against mild infection with SARS-CoV-2. If so, and if it does not change over time, individuals with protective immunity are far more likely to remain protected against severe disease for far longer, even with waning neutralization titers, than to be protected against infection per se.

The researchers project an exponential decay rate after eight months until a ten-year half-life. Against this background, they predict that even without a boost to the immune system, a large percentage of individuals will remain protected against severe infection with a similar strain, requiring only 3% of the initial mean neutralization titer in convalescent patients, even if mild or asymptomatic infection occurs as the titer drops below 20% of the mean convalescent titer.

This study provides a model to use the available limited data on convalescent and vaccination antibody studies in order to predict the course of immunity to the virus.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Fecal matter fights cancer: UPMC researchers look to improve immunotherapy techniques

Fecal matter fights cancer: UPMC researchers look to improve immunotherapy techniques

  • March 15, 2021

While most people flush away their feces without a second thought, a team of UPMC researchers are using them to help improve immunotherapy treatments for cancer patients.

A group of more than 20 scientists at the UPMC Hillman Cancer Center in collaboration with the National Cancer Institute demonstrated a new way of advancing immunotherapy through fecal matter transplants. The group — who started the study in 2016 and began clinical trials in early 2018 — published results from their phase II clinical trial in “Science” in early February.

The research team — led by Pitt scientists Dr. Diwakar Davar and Dr. Hassane Zarour, as well as Dr. Giorgio Trinchieri from the NCI — were looking for a way to improve immunotherapy treatments for patients with advanced melanoma — a form of skin cancer. They inserted healthy gut microbes via injection into cancer patients to replace the “bad” gut microbes, which strengthened their immune systems.

Zarour, a cancer immunologist and professor of medicine at Pitt, said immunotherapy is a technique used to treat cancer where an individual’s immune system is either activated or suppressed through their gut microbes. He said he hopes to use fecal matter transplants to help patients who don’t respond to traditional immunotherapy techniques.

“Cancer immunotherapy is becoming a revolutionary technique in the last 10 years and has been effective in many types of cancers but almost half of the patients do respond to this therapy,” Zarour said. “What we are trying to do is help the other half of the patients who do not respond because we knew that the microbes, particularly the bacteria that you have in your gut, are regulating immunity, including immunity against cancer in the patient, so we hope we can change the bad microbiomes in the gut to good microbiomes.”

Trinchieri, the head of the Cancer Immunology Section at the NCI, said while this application of fecal matter transplants is new to the field of oncology, fecal matter transplants have been used for years to treat diseases such as colitis, inflammatory bowel disease and intestinal infections.

Trinchieri added that patients have given themselves fecal matter transplants in the past to help treat other conditions, but he doesn’t recommend this treatment, nor does the Food and Drug Administration.

“These do-it-yourself methods are about 95% effective and because obviously in theory is that something that you could do on your own, and there are definitely people that have been doing that,” Trinchieri said. “But to do these procedures by yourself in an uncontrolled way is something that can have a major risk, and is definitely a subject that should not be suggested.”

In the clinical trial the team performed, six out of the 15 advanced melanoma patients who received the fecal matter treatment showed either tumor reduction or disease stabilization lasting more than a year. Davar, a medical oncologist and member of the Cancer Immunology and Immunotherapy Program at UPMC Hillman, said the research team hopes to expand the trial to more patients and research whether fecal matter transplants can be applied to other cancers and melanomas as well.

“We also want to expand because our goal is for this treatment to apply to more than one melanoma patient or cancer,” Davar, an assistant professor of medicine at UPMC, said. “Our end goal is to identify the specific microbes that help achieve stronger immunity and create that into some type of pill or probiotic that cancer patients can take in order to boost their ability to fight the disease.”

Although this research discovered a new application for fecal matter treatments, Zarour said the team couldn’t patent this research until the researchers identify an actual product or specific microbe that directly corresponds to more effective immunity, because fecal matter transplants are a commonly used procedure applied to a multitude of conditions.

“If we manage to precisely define a group of microbes that have not been identified yet to be used as probiotics, so then this would be potentially patentable, right, but the process itself is not patentable,” Zarour said.

Trinchieri said this research could potentially have wide-ranging applications and be used to treat more cancers besides melanomas.

“I think that within the next 10 years we will be able to identify the specific set of microbes that help patients who are not able to respond to treatments boost their immunity, and hopefully have this treatment apply to other cancers as well, so that patients who are struggling right now to respond to cancer treatments will have a fighting chance in the future,” Trinchieri said.

capsimmunesystem.org