New therapy extends breast cancer survival rate, prevents reoccurrence

Immune-stimulating drug before surgery shows promise in early-stage pancreatic cancer

  • April 10, 2021

PHILADELPHIA–Giving early-stage pancreatic cancer patients a CD40 immune-stimulating drug helped jumpstart a T cell attack to the notoriously stubborn tumor microenvironment before surgery and other treatments, according to a new study from researchers in the Abramson Cancer Center (ACC) at the University of Pennsylvania. Changing the microenvironment from so-called T cell “poor” to T cell “rich” with a CD40 agonist earlier could help slow eventual progression of the disease and prevent cancer from spreading in more patients.

The data–which included 16 patients treated with the CD40 agonist selicrelumab–was presented today by Katelyn T. Byrne, PhD, an instructor of Medicine in the division of Hematology-Oncology in the Perelman School of Medicine at the University of Pennsylvania, during a plenary session at the American Association for Cancer Research annual meeting (Abstract #CT005).

“Many patients with early-stage disease undergo surgery and adjuvant chemotherapy. But it’s often not enough to slow or stop the cancer,” Byrne said. “Our data supports the idea that you can do interventions up front to activate a targeted immune response at the tumor site–which was unheard of five years ago for pancreatic cancer–even before you take it out.”

The purpose of CD40 agonists is to help “push the gas” on the immune system both by activating antigen-presenting cells, such as dendritic cells, to “prime” T cells and by enhancing immune-independent destruction of the tumor site. The therapies have mostly been investigated in patients with metastatic pancreatic cancer patients in combination with other therapies, such as chemotherapy or other immunotherapies. This is the first time the drug has been shown to drive an immune response in early-stage patients both at the tumor site and systemically–which mirrors what researchers found in their mouse studies.

The phase 1b clinical trial was conducted at four sites, including the ACC, Fred Hutchinson Cancer Research Center at the University of Washington, Case Western Reserve University, and Johns Hopkins University.

Sixteen patients were treated with selicrelumab before surgery. Of those patients, 15 underwent surgery and received adjuvant chemotherapy and a CD40 agonist. Data collected from those patients’ tumors and responses were compared to data from controls (patients who did not receive the CD40 agonist before surgery) treated at Oregon Health and Science University and Dana Farber Cancer Institute.

Multiplex imaging of immune responses revealed major differences between the two groups. Eighty-two percent of tumors in patients who received the CD40 agonist before surgery were T-cell enriched, compared to 37 percent of untreated tumors and 23 percent chemotherapy or chemoradiation-treated tumors. Selicrelumab tumors also had less tumor-associated fibrosis (bundles of tissue that prevent T cells and traditional therapies from penetrating tumors), and antigen-presenting cells known as dendritic cells were more mature.

In the treatment group, disease-free survival was 13.8 months and median overall survival was 23.4 months, with eight patients alive at a median of 20 months after surgery.

“This is a first step in building a backbone for immunotherapy interventions in pancreatic cancer,” Byrne said.

Based on these findings, researchers are now investigating how other therapies combined with CD40 could help strengthen the immune response even further in pancreatic cancer patients before surgery.

“We’re starting to turn the tide,” said Robert H. Vonderheide, MD, DPhil, director of the ACC and senior author. “This latest study adds to growing evidence that therapies such as CD40 before surgery can trigger an immune response in patients, which is the biggest hurdle we’ve faced. We’re excited to see how the next-generation of CD40 trials will take us even closer to better treatments.”

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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.

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.

New therapy extends breast cancer survival rate, prevents reoccurrence

Moffitt investigators identify STING gene methylation allows melanoma to evade the immune system

  • April 8, 2021

TAMPA, Fla. (April 8, 2021) — A dysfunctional immune system significantly contributes to the development of cancer. Several therapeutic strategies to activate the immune system to target cancer cells have been approved to treat different types of cancer, including melanoma. However, some patients do not show beneficial clinical responses to these novel and very promising immunotherapies. In a new article published in Proceedings of the National Academy of Sciences of the United States of America, Moffitt Cancer Center researchers demonstrate how an important defect in STING gene expression in melanoma cells contributes to their evasion from immune cell detection and destruction.

Several different mechanisms have been discovered that allow cancer cells to avoid immune cell detection and destruction, including defective T cell function, losses in expression of key proteins on tumor cells and defective cell signaling in both immune and tumor cells. An important signaling pathway that contributes to interactions between tumor cells and immune cells is the interferon signaling pathway. The interferon pathway increases expression of molecules that allow tumor cells to be recognized and killed by immune cells. One of the key molecules in the interferon signaling pathway is STING, which is activated by the protein cGAS.

Moffitt researchers previously demonstrated that STING activity is commonly suppressed and altered in a subset of melanomas, which prevents the ability of these tumor cells to be targeted by the immune system. The research team wanted to further the understanding of the importance of alterations in STING signaling in melanoma and determine how STING expression becomes suppressed. They focused on a process called epigenetic modification during which methylation groups are added to the DNA regulatory regions of genes, resulting in genes being turned off.

The researchers performed a series of laboratory experiments and discovered that the DNA regulatory region of the STING gene is highly modified by methylation groups resulting in loss of STING gene expression in certain melanoma cell lines. Importantly, they confirmed these findings in patient clinical samples of early and late-stage melanomas and showed similar methylation events and loss of expression of the upstream STING regulator cGAS.

Next, the researchers demonstrated that it is possible to reactivate expression of STING and/or cGAS with a demethylating drug or genetic approaches that overcome methylation. These interventions successfully turned on STING functional activity, resulting in increased interferon levels when triggered by STING agonist drugs that enabled the melanoma cells to now be recognized by immune cells and targeted for destruction.

These findings demonstrate for the first time that a strategy to overcome STING gene methylation can restore interferon signaling and immune cell activity in melanoma and improve a cell-based immunotherapy when combined with STING agonist drugs.

“These studies show the critical importance of an intact STING pathway in melanomas for optimal T cell immunotherapy success, and how to overcome a notable STING defect in melanoma cases of gene hypermethylation by a combination therapy,” said James J. Mulé, Ph.D., senior author and associate center director for Translational Science at Moffitt. “Unless patients’ melanomas are pre-screened for intact versus defective STING, it is not at all surprising that clinical trials of STING agonists have, to date, uniformly failed.”

###

Moffitt collaborated with Glen Barber, Ph.D., from the University of Miami for this study. It was funded by the National Cancer Institute (R01 CA148995, R01 CA184845, P30 CA076292 and P50 CA168536), the Cindy and Jon Gruden Fund, the Chris T. Sullivan Foundation, the V Foundation and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.

About Moffitt Cancer Center

Moffitt is dedicated to one lifesaving mission: to contribute to the prevention and cure of cancer. The Tampa-based facility is one of only 51 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt’s scientific excellence, multidisciplinary research, and robust training and education. Moffitt is the No. 11 cancer hospital and has been nationally ranked by U.S. News & World Report since 1999. Moffitt’s expert nursing staff is recognized by the American Nurses Credentialing Center with Magnet® status, its highest distinction. With more than 7,000 team members, Moffitt has an economic impact in the state of $2.4 billion. For more information, call 1-888-MOFFITT (1-888-663-3488), visit MOFFITT.org, and follow the momentum on Facebook, Twitter, Instagram and YouTube.

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.

Cancer Research Institute and RevImmune Announce Dosing of First Patient in New Phase 2 Study Assessing Therapeutic Benefit of Interleukin-7 in Patients with Cancer and COVID-19

Moffitt Investigators Identify STING Gene Methylation that Allows Melanoma to Evade the Immune System

  • April 8, 2021

Newswise — TAMPA, Fla. (April 8, 2021) — A dysfunctional immune system significantly contributes to the development of cancer. Several therapeutic strategies to activate the immune system to target cancer cells have been approved to treat different types of cancer, including melanoma. However, some patients do not show beneficial clinical responses to these novel and very promising immunotherapies. In a new article published in Proceedings of the National Academy of Sciences of the United States of America, Moffitt Cancer Center researchers demonstrate how an important defect in STING gene expression in melanoma cells contributes to their evasion from immune cell detection and destruction.

Several different mechanisms have been discovered that allow cancer cells to avoid immune cell detection and destruction, including defective T cell function, losses in expression of key proteins on tumor cells and defective cell signaling in both immune and tumor cells. An important signaling pathway that contributes to interactions between tumor cells and immune cells is the interferon signaling pathway. The interferon pathway increases expression of molecules that allow tumor cells to be recognized and killed by immune cells. One of the key molecules in the interferon signaling pathway is STING, which is activated by the protein cGAS.

Moffitt researchers previously demonstrated that STING activity is commonly suppressed and altered in a subset of melanomas, which prevents the ability of these tumor cells to be targeted by the immune system. The research team wanted to further the understanding of the importance of alterations in STING signaling in melanoma and determine how STING expression becomes suppressed. They focused on a process called epigenetic modification during which methylation groups are added to the DNA regulatory regions of genes, resulting in genes being turned off.

The researchers performed a series of laboratory experiments and discovered that the DNA regulatory region of the STING gene is highly modified by methylation groups resulting in loss of STING gene expression in certain melanoma cell lines. Importantly, they confirmed these findings in patient clinical samples of early and late-stage melanomas and showed similar methylation events and loss of expression of the upstream STING regulator cGAS.

Next, the researchers demonstrated that it is possible to reactivate expression of STING and/or cGAS with a demethylating drug or genetic approaches that overcome methylation. These interventions successfully turned on STING functional activity, resulting in increased interferon levels when triggered by STING agonist drugs that enabled the melanoma cells to now be recognized by immune cells and targeted for destruction.

These findings demonstrate for the first time that a strategy to overcome STING gene methylation can restore interferon signaling and immune cell activity in melanoma and improve a cell-based immunotherapy when combined with STING agonist drugs. 

“These studies show the critical importance of an intact STING pathway in melanomas for optimal T cell immunotherapy success, and how to overcome a notable STING defect in melanoma cases of gene hypermethylation by a combination therapy,” said James J. Mulé, Ph.D., senior author and associate center director for Translational Science at Moffitt. “Unless patients’ melanomas are pre-screened for intact versus defective STING, it is not at all surprising that clinical trials of STING agonists have, to date, uniformly failed.”

Moffitt collaborated with Glen Barber, Ph.D., from the University of Miami for this study. It was funded by the National Cancer Institute (R01 CA148995, R01 CA184845, P30 CA076292 and P50 CA168536), the Cindy and Jon Gruden Fund, the Chris T. Sullivan Foundation, the V Foundation and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation.

 

About Moffitt Cancer Center Moffitt is dedicated to one lifesaving mission: to contribute to the prevention and cure of cancer. The Tampa-based facility is one of only 51 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt’s scientific excellence, multidisciplinary research, and robust training and education. Moffitt is the No. 11 cancer hospital and has been nationally ranked by U.S. News & World Report since 1999. Moffitt’s expert nursing staff is recognized by the American Nurses Credentialing Center with Magnet® status, its highest distinction. With more than 7,000 team members, Moffitt has an economic impact in the state of $2.4 billion. For more information, call 1-888-MOFFITT (1-888-663-3488), visit MOFFITT.org, and follow the momentum on Facebook, Twitter, Instagram and YouTube

 

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Cancer Drug Promising for Alzheimer's Disease

Cancer Drug Promising for Alzheimer’s Disease

  • April 7, 2021

A cancer drug used in various types of leukemia to prevent infection is showing promise in Alzheimer’s disease (AD), results of a phase 2 randomized trial suggest.

Investigators found sargramostim (Leukine, Partners Therapeutics), a recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF), provided measurable disease-modifying and memory-enhancing benefits in patients with mild-to-moderate AD.

While the findings are consistent with previous research in mice, “the clinical treatment effect and its speed and extent were novel and unexpected,” the investigators led by Huntington Potter, MD, University of Colorado, Alzheimer’s and Cognition Center in Aurora, note.

The study was published online March 24 in Alzheimer’s & Dementia: Translational Research and Clinical Interventions.

Reduction in AD Pathology

GM-CSF is a hematopoietic and innate immune system modulator and pro-inflammatory cytokine whose beneficial effects on cognition may stem from several different mechanisms.

In neurological injury and disease, GM-CSF has been shown to have anti-apoptotic effects on neurons, to promote neurogenesis and arteriogenesis, and to reduce the formation of glial scars. Just recently, reduced levels of GM-CSF have been found in the cerebrospinal fluid (CSF) of patients with AD.

In prior work with transgenic AD mice, Potter and colleagues observed that daily injections of GM-CSF reduced Alzheimer’s pathology by more than 50% and completely reversed cognitive impairment.

In the phase 2 study, they tested the hypothesis that GM-CSF/sargramostim would stimulate the innate immune system, improve cognition, and reduce pathology in adults with mild-to-moderate AD.

The randomized, double-blind, placebo-controlled trial enrolled 40 adults with mild-to-moderate AD. Half received GM-CSF/sargramostim (250 μg/m2/day subcutaneous injection 5 days a week for 3 weeks) and half received placebo injections.

Follow-up visits occurred at 45 days and at 90 days, with neurological, neuropsychological, blood biomarker, and imaging assessments.

The primary endpoint was safety. Treatment with GM-CSF/sargramostim was safe and well tolerated with no serious adverse events or amyloid-related imaging abnormalities.

The most common sargramostim-related adverse events were dermatological (16 vs 5 placebo), gastrointestinal (8 vs 5), and headache (8 vs 2), as expected for this medication and consistent with the medication’s label.

As expected, GM-CSF/sargramostim treatment increased markers of the innate immune system.

Absolute numbers of monocytes, lymphocytes, and neutrophils were all statistically significantly increased in the sargramostim group vs the placebo group.

Sargramostim treatment also led to statistically significant increases in interleukin (IL)-2, IL-6, and IL-10 and in tumor necrosis factor alpha, as well as a decrease in IL-8.

Although the trial was small and thus inherently underpowered, several efficacy (secondary/exploratory outcomes) were statistically significant in favor of sargramostim.

At the end of treatment, the mean Mini-Mental State Examination (MMSE) total score change in the sargramostim group was 1.45 units higher relative to baseline (P = .0074).

The difference in mean change from baseline in MMSE total scores between the sargramostim and placebo groups was 1.80 (P = .0370) at end of treatment and 1.75 (P = .0272) 45 days later.

In addition to improving cognition, sargramostim modulated blood-based biomarkers of AD neuropathology toward normal; amyloid beta 40, which is decreased in AD, increased 10% (P = .0105) and total tau and ubiquitin C-terminal hydrolase L1 (UCH-L1) decreased 24% (P =.0174) and 42% (P = .0019), respectively, after treatment with sargramostim compared with placebo.

These results suggest that short-term sargramostim treatment leads to “innate immune system activation, cognition and memory improvement, and partial normalization of blood measures of amyloid and tau pathology and neuronal damage” in mild-to-moderate AD, Potter said in a news release from Partner Therapeutics.

The findings have prompted initiation of a larger trial of GM-CSF/sargramostim in AD involving more patients treated over a longer time.

The trial will be funded by the Alzheimer’s Association/Part the Cloud, the University of Colorado, and the Global Down Syndrome Foundation and by a large grant recently awarded from the National Institute on Aging.

Sargramostim is approved by the US Food and Drug Administration and has been used in leukemia patients to reduce the risk of infection. It is not currently approved for treatment of AD.

Promising Preliminary Data

Weighing in on this study and line of research for Medscape Medical News, Mark Forman, MD, PhD, senior director of drug development at the Alzheimer’s Drug Discovery Foundation (ADDF), said Alzheimer’s is a “complicated disease and the ADDF has long believed a combination of drugs addressing multiple targets will be needed for effective treatment.”

Many of the new treatments under investigation are focused on targets associated with the biology of aging, including neuroinflammation, and most studies exploring neuroinflammation are focused on reducing inflammatory responses in the brain, Forman noted.

“However, preliminary animal data from the authors of the current paper suggests that stimulating the immune system with GM-CSF (sargramostim) improves cognition and may reduce Alzheimer’s pathology. There is also similar preclinical data published with G-CSF (filgrastim),” Forman said.

“This is the first clinical study in Alzheimer’s to explore the use of GM-CSF. It was a small study primarily focused on safety and notably, GM-CSF was well-tolerated in the Alzheimer’s population and produced expected pharmacodynamic effects,” Forman said.

The study also generated some “promising effects on clinical endpoints and biomarkers that merit further investigation in a future study. However, the potential for chronic treatment with GM-CSF is unknown, and long-term safety and tolerability in elderly population needs to be defined,” said Forman.

Support for the study was provided by the states of Colorado and Florida, the University of Colorado School of Medicine, the University of Colorado Hospital, the Global Down Syndrome Foundation, the Linda Crnic Institute for Down Syndrome, an Alzheimer’s Association Part the Cloud grant, the Dana Foundation, Don and Sue Fisher, the Hewit Family Foundation, the Sprout Foundation, Marcy and Bruce Benson, Les Mendelson, and other generous philanthropists. This project was also supported by grants from the National Institutes of Health. One author is an employee of Partner Therapeutics. Potter and Forman have disclosed no relevant financial relationships.

Alzheimers Dement (NY). 2021;7(1):e12158. Full text

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Financial Stress and Metastatic Breast Cancer: Tips and More

Financial Stress and Metastatic Breast Cancer: Tips and More

  • April 7, 2021

Metastatic breast cancer (MBC), or stage 4 breast cancer, is cancer that starts in the breasts and spreads to other parts of the body.

Cancer metastasizes, or spreads, when it invades nearby healthy cells, or when the lymph system carries cancerous cells to other parts of the body.

Researchers estimate that about 5 percent of people who receive a breast cancer diagnosis will receive an initial diagnosis of MBC.

Not only can breast cancer cause emotional and mental stress, but it can also lead to financial stress. Here’s how to manage this aspect of a breast cancer diagnosis.

Treatment for MBC can include:

  • chemotherapy
  • radiation
  • surgery

Your oncologist may also recommend targeted drug therapy or immunotherapy. The goal is to strengthen your immune system so your body can fight the cancer, as well as shrink or destroy cancerous cells.

An MBC diagnosis affects people differently, and some are more likely than others to feel a financial strain.

One cause of financial stress is lack of health insurance.

According to a 2018 national survey of more than 1,513 women with MBC, approximately 35 percent didn’t have health insurance. Of those, 70 percent felt concerned about the financial impact of cancer.

Some people with MBC receive treatment for life. This can make the financial cost of stage 4 breast cancer higher than that of stage 1 breast cancer. This, in turn, can lead to an increase in financial stress.

The exact cost of treatment varies. But the monthly cost of treating MBC is about $4,463, compared with only $2,418 for treating stage 1 breast cancer, according to research from 2020.

Common concerns of women who don’t have health insurance include:

  • an inability to pay their medical bills
  • loss of income from not working
  • the fear of collection agencies contacting them

But having health insurance doesn’t necessarily ease financial concerns.

The 2018 national survey found that even people with health insurance experienced financial stress after an MBC diagnosis. In fact, they were more likely to feel stressed about finances.

For some of these women, financial stress was due to concerns over out-of-pocket expenses for treatments.

Even though health insurance covers many cancer-related treatments, most people are still responsible for health insurance deductibles, copayments, and coinsurance.

The possibility of being unable to work during cancer treatments only adds to the stress. For people of higher socioeconomic status, an inability to work coupled with high medical costs often triggers worries about losing assets, too.

Stress is a natural response. Stressful situations trigger a fight-or-flight reaction, where your body releases adrenaline, cortisol, and other hormones to help you respond to possible threats.

While short-term, or acute, stress isn’t usually harmful, chronic stress means your body’s stress response doesn’t shut off.

This can lead to too much cortisol and adrenaline, which triggers an inflammatory state. And according to a research review from 2010, chronic inflammation may lead to tumor growth and cause cancer to spread.

Too many stress hormones can also inhibit anoikis, a process that signals the death of cells. It occurs when normal cells migrate to a place they don’t belong. When stress hormones prevent this process from happening, this can lead to uncontrolled cancer growth and spread.

It’s important to learn healthy ways to manage your stress. Here’s a look at several ways to help relieve stress after a diagnosis of breast cancer.

Exercise

Light to moderate exercise may improve sleep, increase your energy, and relieve stress. You can practice indoors or go for a walk outdoors to get fresh air.

Exercise releases hormones such as endorphins and dopamine. These are feel-good hormones that can improve your mental outlook.

Practice self-care

Taking care of your body and mind can also relieve stress. Spend more time focusing on yourself and take part in hobbies you enjoy or other relaxing activities.

In addition, you can practice mindfulness techniques. Listen to calm music, meditate, or practice deep breathing exercises.

Know your limitations

If you’re not feeling well, it’s OK to say no. Overbooking yourself or taking on too many tasks can be overwhelming and increase stress.

Get enough sleep

Lack of sleep can also worsen stress. Aim for at least 7 hours or more of sleep each night.

To improve sleep quality, limit daytime naps, avoid heavy meals and liquids close to bedtime, and make your room as comfortable as possible. It’s best to keep it cool, dark, and quiet.

Don’t isolate yourself

Spending time with close family and friends can take your mind off your worries. Plus, it often helps to talk with someone and share your experience. If you don’t feel comfortable speaking with a friend or family member, join a support group, whether in-person or online.

If you’re unable to cope with the emotional, mental, physical, or financial stress of MBC, talk with your doctor.

Resources are available to help you cope with stress.

Your doctor may recommend talk therapy, support groups, or cognitive behavioral therapy. They may also be able to provide information on resources to help you manage the costs of cancer care.

A diagnosis of MBC can have a huge financial impact. Whether you’re lacking insurance or facing expensive out-of-pocket costs even with insurance, you may worry about the long-term effects of MBC on your finances.

Learning how to manage financial stress is key to coping with your diagnosis, so take steps to reduce your stress levels. And if necessary, speak with your doctor for help.

Biomaterials bolster the battle against cancer

Biomaterials bolster the battle against cancer

  • April 5, 2021
April 5, 2021

According to Abhinav Acharya, an assistant professor of chemical engineering at Arizona State University, “a single form of treatment is often not sufficient to defeat a given form of cancer.”

“We need a combinatorial approach, meaning the use of two or more therapies together.”
Artistic rendition of new technologies that will advance cancer treatments
ASU Assistant Professor Abhinav Acharya is developing novel technologies that will permit the simultaneous use of cancer vaccines and chemotherapy treatments. Graphic by Rhonda Hitchcock-Mast/ASU
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For example, the tandem application of chemotherapy with immunotherapy or vaccine use could be much more effective than either measure alone. But the problem, Acharya said, is that each of these therapies is so taxing on the human immune system that they can’t be deployed simultaneously with a patient.

Solving this problem is the focus of a new project that Acharya is leading with the support of a grant from the National Institutes of Health. He is developing the first biomaterials-based technologies to modulate the functions of immune system cells in a way that can enable safe and effective combinations of clinical treatments to battle melanoma, ovarian cancer and potentially many other ailments.

Acharya works at the interface of materials science and immunology in the School for Engineering of Matter, Transport and Energy, one of the six Ira A. Fulton Schools of Engineering at ASU. His research for this NIH project focuses on cancer vaccines and applying the functions of their two major components: antigens and adjuvants.

Antigens trigger the immune system to create antibodies that attack a specific pathogen or toxin. These substances might take the form of inactive components from the targeted pathogen itself or, in the case of Acharya’s work, drugs tailored to induce a desired defense response.

Adjuvants are salt- or emulsion-based vaccine components that stimulate and amplify the immune system’s response to the particular pathogen targeted by the antigens. In other words, antigens identify the foe and adjuvants fuel the fight.

Part of Acharya’s work is developing novel adjuvants based on polymeric biomaterials generated from central carbon metabolites. The resulting polymers act as a source of cellular nutrients, and they can be fabricated either as microparticles or nanoparticles depending on their purpose.

“If the particles are micron-sized, they mimic the size of bacteria. If they are nanoparticles, they mimic the size of viruses,” Acharya said. “In either case, the immune system sees this foreign material as a threat and tries to digest it.”

This act of consumption is the key to delivering biomaterial-based nutrients to the body’s immune system when it is dampened during chemotherapy treatment. These nutrients can restore the chemo-suppressed metabolic pathways that enable sentinel-like dendritic cells to sound the alarm and prompt T-cells, a form of white blood cells, to fight the cancer.

Alongside rescuing the metabolic processes that help boost the body’s defenses, another goal is to disrupt the equivalent pathways that feed cancer cells. This latter task shapes three aims of this project, which specifically seeks to improve skin cancer treatment.

The first aim is to formulate and deliver a drug that disrupts a particular enzyme in the metabolic pathway of cancer cell glycolysis, which is the conversion of glucose into adenosine triphosphate, or ATP, a key fuel for cellular life. Halting this energy production pathway starves the cancer of the energy it needs to proliferate.

The second aim is similarly to formulate and deliver a drug targeting an enzyme in the metabolic pathway of cancer cell glutaminolysis, which is another means to generate ATP and other cancer-sustaining molecules within a tumor.

“And the third aim is to demonstrate that we can achieve these formulations at a scale to permit production for clinical use,” Acharya said.

Challenges to this work include generating a T-cell response that is robust enough to operate effectively in the context of both chemotherapy and the nutrient-deficient environment that the enzyme-targeting technology is creating in and around a tumor. But Acharya is confident of success after positive initial tests with cancerous human tissue in a laboratory setting.

Additionally, his interdisciplinary view of research already points to other applications for the innovations emerging from the NIH project.

“This is really a platform technology, so we can develop metabolic-modifying biomaterials for many purposes,” he said. “We are working right now with Dr. Marion Curtis, an immunologist with Mayo Clinic, to determine how to deploy this new technology against other types of cancers. As well, there may be new remedies for traumatic brain injuries and opportunities to better combat autoimmune diseases, rheumatoid arthritis, multiple sclerosis and so much more. The potential is very exciting.”

Children's immune response more effective against COVID-19 -- ScienceDaily

Expands understanding of immune responses in cancer and other diseases — ScienceDaily

  • April 5, 2021

Researchers at the Bloomberg~Kimmel Institute for Cancer Immunotherapy at the Johns Hopkins Kimmel Cancer Center have developed DeepTCR, a software package that employs deep-learning algorithms to analyze T-cell receptor (TCR) sequencing data. T-cell receptors are found on the surface of immune T cells. These receptors bind to certain antigens, or proteins, found on abnormal cells, such as cancer cells and cells infected with a virus or bacteria, to guide the T cells to attack and destroy the affected cells.

“DeepTCR is an open-source software that can be used to answer questions in research into infectious disease, cancer immunology and autoimmune disease; any place where the immune system has a role through its T-cell receptors,” said lead study author John-William Sidhom, an M.D./Ph.D. student at the Johns Hopkins University School of Medicine and Department of Biomedical Engineering working in the Bloomberg~Kimmel Institute for Cancer Immunotherapy.

The research was published March 11 in Nature Communications.

Sidhom was inspired to develop the software after attending a presentation on the use of deep learning for the medical sciences at the 2017 meeting of the American Association for Cancer Research. “I was doing research on T-cell receptor sequencing, and it struck me that this was the right technology to better analyze T-cell sequencing data,” he says.

Deep learning is a form of artificial intelligence that roughly mimics the workings of the human brain in terms of pattern recognition. “Deep learning is a very flexible and powerful way to do pattern recognition on any kind of data. In this paper, we use deep learning to identify patterns in sequencing data of the T-cell receptor,” says Sidhom, adding that the way the software explores T-cell receptors is analogous to an internet search. “When someone performs an internet search for an image of cats or dogs, the query doesn’t involve looking for images that have a caption that labels the image as a cat or dog, but rather applies an algorithm that explores the features of the images and recognizes patterns that identify the images as a cat or dog. This is deep learning.”

DeepTCR is a comprehensive deep-learning framework that includes both unsupervised and supervised deep learning models that can be applied at the sequence and sample level. Sidhom says the unsupervised approaches allow investigators to analyze their data in an exploratory fashion, where there may not be known immune exposures, and the supervised approaches will allow investigators to leverage known exposures to improve the learning of the models. As a result, he says, DeepTCR will enable investigators to study the function of the T-cell immune response in basic and clinical sciences by identifying the patterns in the receptors that confer the function of the T cell to recognize and kill pathological cells.

One of the main challenges of analyzing TCR sequencing data is distinguishing meaningful sequencing data from inconsequential data, and DeepTCR helps perform this analysis. “There are a lot of sequences in someone’s immune repertoire. There are a lot of pathogens that someone can be infected by, so the immune response is very broad. As a result, there is a sea of noise in the immune response, and only parts of it are important at a certain time for a certain infection,” Sidhom explains. “I may have T-cell responses to a thousand different viruses, but when the flu impacts me, I only need to utilize a small subset of those T cells to fight the flu. The main thing that the algorithm can do is isolate and match the right T cells to specific responses.”

The software package, which employs a type of deep-learning architecture called a convolutional neural network, provides users the ability to find T-cell sequencing patterns that are relevant to a specific exposure, like a flu infection, a cancer or an autoimmune disease.

“When presented with a lot of data, our algorithms can learn rules of these TCR sequence patterns. For example, we may not know the rules for how the body responds to flu, but with enough data, our software can learn those rules and then teach us what they are,” says Sidhom. “It is very well-suited to identify complex patterns in a very, very large immune repertoire to identify the interacting partners between a T-cell receptor and its antigen.”

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Cancer Research Institute and RevImmune Announce Dosing of First Patient in New Phase 2 Study Assessing Therapeutic Benefit of Interleukin-7 in Patients with Cancer and COVID-19

Cancer Research Institute and RevImmune Announce Dosing of First Patient in New Phase 2 Study Assessing Therapeutic Benefit of Interleukin-7 in Patients with Cancer and COVID-19

  • March 30, 2021

NEW YORK and BETHESDA, Maryland, March 30, 2021 — The Cancer Research Institute (CRI), a nonprofit organization dedicated to the discovery and development of powerful immunotherapies for all cancers and RevImmune, Inc., a privately held biotech company focused on T-cell technology and development, announced today the dosing of the first patient in a new study designed to assess the therapeutic benefit of interleukin-7 (IL-7) in cancer patients with COVID-19. This stems from a new understanding that patients with severe COVID-19 have low levels of T cells and exhausted T cells, and these patients benefit from therapies that focus on augmenting the cellular immune response, rather than solely therapies that dampen the immune system.

The Phase 2 multi-center clinical trial called “ILIAD-7-US-O” will evaluate the clinical benefit of RevImmune’s product candidate CYT107 in approximately 48 patients living with cancer. CYT107 is a therapeutic form of the master growth factor for human T cells, IL-7, and this is the first study to test an IL-7 drug specifically in people with cancer who also have COVID-19. The clinical trial is funded by CRI’s Clinical Accelerator, a program that supports and coordinates early-phase clinical trials of promising immuno-oncology combination therapies.

“This partnership allows CRI to apply RevImmune’s promising IL-7 agent in a novel setting of patients with both cancer and COVID-19, potentially offering a way to strengthen the immune system’s ability to fend off the SARS-CoV-2 coronavirus, mitigate symptoms of COVID-19, and improve overall outcomes for people living with cancer and COVID,” said Jay Campbell, managing director of CRI’s Venture Fund and Anna-Maria Kellen Clinical Accelerator.

Common cancer treatment regimens can compromise a patient’s immune system, including reductions in lymphocyte counts, such as T cells, a condition known as lymphopenia. Similarly, COVID-19 can lead to dysregulation of the adaptive immune system, which can also result in patients becoming lymphopenic. The profound and protracted lymphopenia experienced in COVID-19 patients has been correlated with increased secondary infections and death. Furthermore, surviving lymphocytes have severely impaired anti-viral function and are exhausted, ultimately resulting in immune system collapse.

IL-7 has been shown to provide a rapid and durable restoration of functional immune cells, predominantly CD4+ and CD8+ T cells, which are able to fight the primary viral infection and secondary infections. In previous clinical studies, CYT107 has demonstrated the ability to quickly restore immune function, such as increasing the number and diversity of T cells in patients, including those with low and exhausted T cell levels. CYT107 has been shown to be safe and well-tolerated and patients experienced durable long-lasting responses.

Researchers involved in the ILIAD-7 study hope CYT107 will provide the same benefit to cancer patients with COVID-19, with the aim of reducing risk of progressing to severe stages of COVID-19.

“The medical community has learned a great deal about COVID-19 as a disease this past year and has come to realize that patients who develop severe COVID-19 symptoms have impaired immune systems, including exhausted and depleted T-cells,” said Michel Morre, D.V.M., M.Sc., chief scientific officer at RevImmune. “Therapies like IL-7 reinvigorate and expand the cellular immune response to the infection, and we are excited for the opportunity to continue to follow the science and evaluate a potential treatment option for those affected by both COVID-19 and cancer.”

About the ILIAD-7-US-O Study
The ILIAD-7-US-O study tests RevImmune’s recombinant interleukin-7 product, CYT107, on patients with cancer and lymphopenic (with low lymphocyte counts) COVID-19. The trial aims to compare the effects of CYT107 versus placebo at producing immune reconstitution by restoring lymphocyte function and increasing lymphocyte proliferation in oncology patients, where their cancer is being or has been treated with standard of care therapies. The trial hopes to observe a possible clinical improvement as patients with restored lymphocyte counts should better eliminate invading pathogens such as SARS-CoV-2. Approximately 48 patients will be randomized 1:1 to receive either CYT107 or placebo at two trial sites: Memorial Sloan Kettering Cancer Center in New York City and The University of Texas MD Anderson Cancer Center in Houston, Texas, with Stephen Pastores, M.D., and Cristina Gutierrez, M.D., as Principal Investigators, respectively. The clinical trial is funded by the CRI Anna-Maria Kellen Clinical Accelerator, a program that supports and coordinates early-phase clinical trials of promising immuno-oncology combination therapies.

About the Cancer Research Institute
The Cancer Research Institute (CRI), established in 1953, is a top-rated U.S. nonprofit organization dedicated exclusively to saving more lives by fueling the discovery and development of powerful immunotherapies for all cancers. Guided by a world-renowned Scientific Advisory Council that includes four Nobel laureates and 27 members of the National Academy of Sciences, CRI has invested $445 million in support of research conducted by immunologists and tumor immunologists at the world’s leading medical centers and universities and has contributed to many of the key scientific advances that demonstrate the potential for immunotherapy to change the face of cancer treatment. To learn more, go to cancerresearch.org.

About the CRI Anna-Maria Kellen Clinical Accelerator
CRI’s clinical program, the Anna-Maria Kellen Clinical Accelerator, is a unique academia-nonprofit-industry collaboration model that serves as an “incubator” that delivers multi-center clinical trials for promising new immunotherapy combinations. CRI’s venture philanthropy fund supports clinical trials within this program, which fosters a collaborative environment that enables scientists to advance their most ambitious research ideas and accelerates studies that one group or company could not do alone. To learn more about the CRI Anna-Maria Kellen Clinical Accelerator, go to cancerresearch.org/clinical-accelerator.

About RevImmune
RevImmune is a privately held biotech company based in France, the U.S. and the U.K. RevImmune is in multiple Phase II trials with CYT107 for treatment of sepsis, certain infectious diseases, and certain cancers. Over 500 patients have been treated with CYT107 in RevImmune’s prior and current trials for multiple different viral diseases and sepsis. CYT107 showed an excellent safety profile and encouraging results in those trials. To learn more, go to revimmune.com.

Media Contacts:
For Cancer Research Institute: Brian Brewer, +1-212-688-7515 x242, bbrewer@cancerresearch.org
For RevImmune: Michel Morre, +33 6 03 35 70 60, mmorre@revimmune.com

 

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