Anti-TIGIT and ICI Combinations Supported by Early-Phase Research

Anti-TIGIT and ICI Combinations Supported by Early-Phase Research

  • June 15, 2021

Immunotherapy treatments have generated excitement by eliciting durable responses in various tumor types, making a significant contribution to the progress of oncology.1,2 However, monotherapy with anti–PD-1/PD-L1 and anti–CTLA-4 monoclonal antibodies has yielded low response rates, mainly due to insufficient immune activation.1,3 There is hope that these poor monotherapy response rates will significantly improve when these agents are combined with T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) inhibitors, which are next-generation immune checkpoint antibodies (FIGURE 14).

“I do believe that PD-1 and PD-L1 inhibitors are really the first step in understanding how a cancer interacts with a patient’s immune system,” said Melissa Johnson, MD, program director of lung cancer research and of the Solid Tumor Immune Effector Cellular Therapy Program at Sarah Cannon Research Institute in Nashville, Tennessee, in an interview with Targeted Therapies in Oncology (TTO). “There’s so much more to learn, and there are many patients who aren’t benefiting from PD-1/ PD-L1 inhibitors. We owe it to them especially to keep looking and to keep evaluating strategies that would also stimulate their immune system in the same way.”

To increase response rates, immune checkpoint inhibitors have been used in combination with chemotherapy or other immune checkpoint inhibitors, although this strategy has led to more adverse events (AEs).1 Additionally, although some patients with metastatic melanoma have seen increased response rates with the combination of ipilimumab (Yervoy) and nivolumab (Opdivo) compared with either monotherapy, a substantial number of patients remained unresponsive. In an area of ongoing research, combinations of immune checkpoint inhibitors are being evaluated for their ability to further stimulate the immune system.

“It is clear that only a small subset of patients respond to PD-1 [inhibitors] alone. Understanding how to use the other immune cells, particularly the Tregs, which regulate other cells in the immune system, to jump-start immunotherapy makes good sense and is an avenue we are excited about,” Jyoti Patel, MD, said in an interview with TTO. Patel is a professor of medicine and the associate vice chair for clinical research in the Department of Medicine at Northwestern University Feinberg School of Medicine and the medical director of thoracic oncology and assistant director for clinical research at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, Illinois.

Recent research has identified TIGIT as a promising emerging immune checkpoint target. TIGIT indirectly suppresses T-cell activation and is expressed on multiple types of immune cells, including regulatory T (Treg) cells, activated T cells, and natural killer (NK) cells.1,5 TIGIT is upregulated in T cells and NK cells after ligand binding, inhibiting these cells’ ability to kill tumor cells.2 Increased TIGIT expression is also associated with advanced disease and poor survival outcomes. Additionally, increased TIGIT expression after treatment is associated with disease recurrence. TIGIT and its coreceptors, including CD226 and CD96, interact with a group of ligands expressed on tumor cells: nectins and nectin-like molecules, including poliovirus receptor (PVR), the main TIGIT ligand. PVR ligands binding to TIGIT suppresses the antitumor immune response of the TIGIT-expressing cell; in contrast, ligand binding to CD226 triggers immune cell activation. Thus, TIGIT and CD226 oppose each other to regulate tumor immunity.1,2 Anti-TIGIT therapy is presumed to invigorate immune function and enhance the activity of T cells and NK cells.2

The most promising data have come from tiragolumab, an anti-TIGIT antibody, in combination with atezolizumab (Tecentriq), an anti–PD-L1 antibody. Immunotherapy combinations featuring dual blockade of TIGIT and PD-1/PD-L1 are promising due to their synergistic enhancement of antitumor responses.1,6

“We have great comfort and a lot of options with checkpoint inhibitors targeting PD-1 and PD-L1, but it seems that [targeting the TIGIT] pathway in this combinatorial approach will be well tolerated, unlike using CTLA-4 with PD-L1,” Patel said. “Anti-TIGIT therapy is exciting because we see it as a complement with PD-1 blockade in the wide variety of tumors in which we’ve seen efficacy. It seems that by inhibiting TIGIT, we may again improve PD-1 efficacy.”

Tiragolumab was the first anti-TIGIT antibody to receive the FDA’s breakthrough therapy designation, based on findings from the CITYSCAPE trial (NCT03563716).7 CITYSCAPE (n = 135) was a prospective, randomized, double-blind, placebo-controlled, phase 2 trial in patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) who were chemotherapy naive with PD-L1positive status (percentage of tumor cells expressing PD-L1 or tumor proportion score [TPS], ≥ 1%) and wild-type EGFR and ALK.8 Results demonstrated that the objective response rate (ORR) was improved in patients randomized to the tiragolumab and atezolizumab (TA) group (n = 67) compared with the placebo and atezolizumab (PA) group (n = 68), at 37.3% versus 20.6%, respectively (odds ratio, 2.57; 95% CI, 1.07-6.14). Patients in the TA group also had improved median progression-free survival (mPFS) compared with PA (5.6 months vs 3.9 months; HR, 0.57; 95% CI, 0.37-0.90).

“Although there have been other checkpoint inhibitors that have been developed to try to amplify the antitumor immune response achieved by PD-1 and PD-L1 inhibitors, there are very few that actually work,” Johnson said. “The CITYSCAPE data presented at ASCO [American Society of Clinical Oncology meeting] in 2020 showed that the addition of the anti-TIGIT tiragolumab to atezolizumab improved responses and progression-free survival in patients who had PD-L1–expressing tumors. [The results of CITYSCAPE] suggest there is, in fact, a way to push those tumors that are immune sensitive a little bit further.

“Perhaps the most impressive thing about the CITYSCAPE data was the exploratory analysis in the [patients with] PD-L1–high [tumors, which] express PD-L1 at greater than 50%. The response rates were 66% in the combination group and 24% in atezolizumab alone. The [median] PFS was not reached when patients were treated with the combination, and it was 4 months for patients treated in the atezolizumab arm, suggesting that the [patients with] PD-L1–high [tumors] are the ones [who] benefit the most from [a TIGIT and PD-L1 blockade] strategy,” Johnson continued.

The safety profiles of the 2 groups in CITY-SCAPE were comparable.8 Most patients in both groups experienced treatment-related AEs (TRAEs), 80.6% in the TA group and 72% in the PA group.

“The most common [adverse] effects were what you would expect from immune-mediated therapy, like rash and thyroid issues,” Johnson said. “Most commonly, infusion reactions were seen, and that typically was with the first dose only and not with subsequent infusions. Some soft stool and diarrhea [were reported as well]. There were very few cases of more severe immune- related toxicities, like hepatitis.”

“The toxicity seems quite manageable, and we’re seeing improvements in both progression-free survival and response,” Patel added.

“My sense is that we can expect the [combination of tiragolumab and atezolizumab to be used in future practice] without toxicity rates of 30% like we’ve seen for ipilimumab and nivolumab. I think that’s certainly led to enthusiasm in larger phase 3 studies,” she said.

Ongoing Trials

Several trials are currently evaluating the use of tiragolumab in different combinations in the frontline setting to determine the efficacy of TIGIT and PD-1/PD-L1 combination therapy.

“I could envision that [tiragolumab] could be added to the armamentarium in a lot of ways,” Johnson said. “It just depends on what some of these trials show us about where the benefit is the greatest.…There are lots of things that one can do with a checkpoint inhibitor once you figure out where it’s the most useful. It’s an exciting discovery.”

One notable tiragolumab trial, SKY-SCRAPER-01 (NCT04294810), is a double-blind, randomized, placebo-controlled, phase 3 trial evaluating the frontline use of tiragolumab and atezolizumab compared with placebo and atezolizumab in advanced, PD-L1–high NSCLC. The trial is expected to enroll 560 patients, with primary outcomes of PFS and overall survival (OS).

“The SKYSCRAPER-01 trial that’s enrolling right now in frontline lung cancer is a really important trial. [The trial investigators hope] to see a significant difference between atezolizumab and tiragolumab compared with atezolizumab alone,” Johnson said.

Vibostolimab

Another anti-TIGIT antibody with encouraging results in NSCLC is vibostolimab. The ongoing, multicohort, phase 1 MK-7684-001 trial (NCT02964013) is evaluating vibostolimab in patients with advanced solid tumors, and results from the dose-confirmation/expansion phase in patients with NSCLC were recently published. One report described evaluation of vibostolimab as either monotherapy or in combination with pembrolizumab (Keytruda) in 79 heavily pretreated patients with anti–PD-1/PD-L1–refractory disease.9 The majority of patients (78%) had received at least 2 prior lines of therapy. The ORR was 7% (95% CI, 2%-20%) for vibostolimab monotherapy (n = 41) and 5% (95% CI, <1%-18%) for combination therapy (n = 38). AEs occurred in at least 97% of patients, and at least 65% experienced TRAEs. Common TRAEs included pruritus, fatigue, rash, arthralgia, and decreased appetite. Grade 3 to 4 TRAEs occurred in 10 patients, with lipase increase and hyper-tension being the most common.

Discussing the optimal sequencing of checkpoint inhibitors in therapy, Johnson said, “what we’re finding with lots of check-point inhibitors is that it’s not enough to restore an immune response to a cancer that has developed resistance to a PD-1 inhibitor alone.…We’ll have to find other therapies for patients with acquired resistance to PD-1 inhibitors, rather than trying to continue them and add other checkpoint inhibitors to them. I don’t think there’s been much success with many checkpoint inhibitors [used as therapy for PD-1– or PD-L1–refractory disease].”

In another report of results from the MK-7684-001 study, 41 anti–PD-1/PD-L1–naive patients with advanced NSCLC all received the vibostolimab-pembrolizumab combination.10 The majority of patients (73%) had received at least 1 prior treatment regimen. Results demonstrated an ORR of 29% (95% CI, 16%-46%). Patients with PD-L1–positive tumors (TPS ≥ 1%) had an ORR of 46% (95% CI, 19%-75%), whereas their PD-L1–negative counterparts (TPS < 1%) had an ORR of 25% (95% CI, 5%-57%).

The mPFS for the entire cohort was 5.4 months (95% CI, 2.1-8.2). PD-L1–positive patients had an mPFS of 8.4 months (95% CI, 3.9-10.2), double the PD-L1–negative mPFS of 4.1 months (95% CI, 1.9-not reached). TRAEs occurred in 83% of patients, with the most common being pruritus, hypoalbuminemia, and pyrexia. Serious grade 3 to 4 TRAEs occurred in 15% of patients. Investigators concluded that the combination therapy was well tolerated and had promising antitumor activity.

“Vibostolimab has certainly caught our attention…seeing [that] the drug was well tolerated and improved response rates,” Patel said.

Domvanalimab

Another noteworthy anti-TIGIT antibody is domvanalimab. This agent is currently being evaluated in patients with PD-L1–positive, locally advanced or metastatic, treatment-naive NSCLC in the ARC-7 trial (NCT04262856).

This open-label, randomized phase 2 trial includes 3 study arms: zimberelimab (anti–PD-1) monotherapy, domvanalimab with zimberelimab, and domvanalimab with zimberelimab and etrumadenant (a dual–adenosine receptor antagonist). The study is expected to enroll approximately 150 patients (FIGURE 2).

In Development

Multiple new anti-TIGIT antibodies are in the pipeline. Data presented at the American Association for Cancer Research Annual Meeting 2021 highlighted early-phase clinical and preclinical trials evaluating TIGIT- targeting antibodies.

“There are other TIGIT antibodies…and whether they work the same or not, we’re still learning,” Johnson said.

EOS884448 (EOS-448) is a potent anti-TIGIT antibody that was evaluated as monotherapy in a multicenter, open-label, phase 1/2 study in patients with previously treated advanced solid malignancies (NCT04335253). Preliminary dose-escalation results (n = 22) demonstrated no dose-limiting toxicity at any of the 5 dose levels tested and pharmacokinetic analyses indicated dose-proportional increases in plasma EOS-448.11 The patients received EOS-448 intravenously once every 2 weeks or once every 4 weeks according to their dose and schedule allocation. Doses of 20, 70, 200, 700 mg once every 2 weeks and 1400 mg every 4 weeks were evaluated. Depletion of suppressive Treg cells was observed at all dose levels. Additionally, the optimal dosing interval was found to be every 3 or 4 weeks. Patients had received a median of 3 lines of therapy prior to treatment with EOS-448.

Investigator assessment of 20 response-evaluable patients demonstrated stable disease in 9 patients and a partial response in 1 patient with melanoma previously treated with pembrolizumab. No immunogenicity was observed in any patients. Treatment-related AEs (TEAEs) occurred in 82% of patients, with pruritus, infusion- related reaction, fatigue, and pyrexia being the most common. The majority (52%) of patients with TEAEs had grade 3 or higher, with serious TEAEs occurring in 36%. Investigators concluded that these preliminary data support further exploration of EOS-448 in clinical trials.

One tumor type of interest in TIGIT research is breast cancer. Triple-negative breast cancer (TNBC) is a particular focus because immunotherapy has proven highly beneficial in that patient population. Additionally, there is increased expression of TIGIT in malignant breast tissue compared with normal tissue, further highlighting the potential for use of TIGIT-targeting therapeutics in this patient population.

Another study evaluated mRNA expression of members of the TIGIT/PVR/NECTIN family in breast tumors from 1904 patients using a publicly available data set.12

Comparison of results in different breast cancer subtypes demonstrated that most TIGIT/PVR/NECTIN genes had the highest expression levels in TNBC, followed closely by HER2-positive breast cancer. Hormone receptor–positive breast cancer had the lowest expression. No association was found between expression of most TIGIT/PVR/ NECTIN genes and OS across breast cancer subtypes. However, expression of the costimulatory receptor CD226 was associated with significantly improved OS in early TNBC (HR, 0.69; 95% CI, 0.48-0.99).

The investigators concluded that combination therapy targeting TIGIT and PD-1/ PD-L1 may provide improved efficacy in patients with TNBC.

“In triple-negative breast cancer, there’s been some question about the efficacy of immunotherapies,” Patel said. “Many of these tumors may look cold, and inhibition of TIGIT, which is suppressing the immune reaction, might make sense to make [the tumor microenvironment] more immune favorable.”

HLX53 is a novel single-domain antibody that binds TIGIT strongly, blocking binding of its ligands CD155 (NECTIN5) and CD112 (NECTIN2), thus preventing TIGIT from inhibiting the antitumor immune response. Combining HLX53 with an anti–PD-L1 antibody showed a synergistic effect on tumor inhibition.13

Another anti-TIGIT antibody with promising preclinical data is SEA-TGT.14 Its distinct, nonfucosylated antibody backbone was shown to confer enhanced antitumor activity, including Treg depletion, compared with standard-format anti-TIGIT antibodies.

A phase 1 trial (NCT04254107) has been initiated to investigate SEA-TGT alone and in combination with pembrolizumab. The study protocol was presented at the 2021 ASCO Annual Meeting.

Other anti-TIGIT therapies include etigilimab and BMS-986207. Etigilimab is currently undergoing evaluation with nivolumab in an open-label, multicenter, phase 1/2 basket study (NCT04761198) in patients with advanced solid tumors. This trial has an estimated enrollment of 125 patients.

In another phase 1/2 open-label trial (NCT04570839), BMS-986207 is being evaluated in combination with nivolumab and COM701, an inhibitor of PVRIG (a TIGIT coreceptor that binds NECTIN2). To be eligible for study, patients must have high tumor expression of NECTIN2. The investigators plan to accrue 100 patients with advanced solid tumors for the trial.

“There are a number of exciting compounds. Right now they seem to be improving response rates compared with PD-L1 inhibitors or PD-1 inhibitors alone,” Patel said.

“I think…we need to see more mature data in a larger group of patients and actually have [an] eye toward the patient selection for these compounds because [they are] clearly efficacious. We just have to understand in whom monotherapy would be more effective [compared with combination therapy].”

References

1. Rotte A, Jin JY, Lemaire V. Mechanistic overview of immune checkpoints to support the rational design of their combinations in cancer immunotherapy. Ann Oncol. 2018;29(1):71-83. doi:10.1093/ annonc/mdx686

2. Yeo J, Ko M, Lee DH, Park Y, Jin HS. TIGIT/CD226 axis regulates anti-tumor immunity. Pharmaceuticals (Basel). 2021;14(3):200. doi:10.3390/ph14030200

3. Ventola CL. Cancer immunotherapy, part 3: challenges and future trends. P&T. 2017;42(8):514-521.

4. Gorvel L, Olive D. Targeting the “PVR-TIGIT axis” with immune checkpoint therapies. F1000Res. 2020;9:F1000 Faculty Rev-354. doi:10.12688/f1000research.22877.1

5. Qin S, Xu L, Yi M, Yu S, Wu K, Luo S. Novel immune checkpoint targets: moving beyond PD-1 and CTLA-4. Mol Cancer. 2019;18(1):155. doi:10.1186/s12943-019-1091-2

6. Chauvin JM, Zarour HM. TIGIT in cancer immunotherapy. J Immunother Cancer. 2020;8(2):e000957. doi:10.1136/jitc-2020-000957

7. Roche’s novel anti-TIGIT tiragolumab granted FDA breakthrough therapy designation in combination with Tecentriq for PD-L1-high non-small cell lung cancer. News release. Roche. January 5, 2021. Accessed April 26, 2021. https://bit.ly/3hmWDm3

8. Rodriguez-Abreu D, Johnson ML, Hussein MA, et al. Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). J Clin Oncol. 2020;38(suppl 15):9503. doi:10.1200/JCO.2020.38.15_suppl.9503

9. Ahn M, Niu J, Kim D, et al. Vibostolimab, an anti-TIGIT antibody, as monotherapy and in combination with pembrolizumab in anti-PD-1/PD-L1-refractory NSCLC. Ann Oncol. 2020;31(suppl 4):S887. doi:10.1016/j.annonc.2020.08.1714

10. Niu J, Nagrial A, Voskoboynik M, et al. Safety and efficacy of vibostolimab, an anti-TIGIT antibody, plus pembrolizumab in patients with anti-PD-1/PD-L1-naive NSCLC. Ann Oncol. 2020;31(suppl 4):S891-S892. doi:10.1016/j.annonc.2020.08.1724

11. Van den Mooter TFA, Migeotte A, Jungles C, et al. Preliminary data from phase I first-in-human study of EOS884448, a novel potent anti-TIGIT antibody, monotherapy shows favorable tolerability profile and early signs of clinical activity in immune-resistant advanced cancers. Poster presented at: American Association for Cancer Research (AACR) Annual Meeting 2021; April 10-15, 2021; virtual.

12. DuPree K, Molinero L. TIGIT/PVR/NECTIN immune checkpoint axis expression across breast cancer subtypes. Poster presented at: AACR Annual Meeting 2021; April 10-15, 2021; virtual.

13. Hua B, Yang M, Xue J, et al. A novel single-domain antibody targeting TIGIT for cancer use in combination therapies. Poster presented at: AACR Annual Meeting 2021; April 10-15, 2021; virtual.

14. Smith A, Zeng W, Lucas S, et al. SEA-TGT is an empowered anti-TIGIT antibody that displays superior combinatorial activity with several therapeutic agents. Poster presented at: AACR Annual Meeting 2021; April 10-15, 2021; virtual.

Intralesional Therapies Help Bridge the Gap Between Improved Results and Less Toxicity

Intralesional Therapies Help Bridge the Gap Between Improved Results and Less Toxicity

  • June 15, 2021

In 2011, when Harry Clark was 60 years old, he noticed a mole on his right shin. Even though he grew up under the hot Tucson, Arizona, sun and jokes that he lost his dark bronze tan every November, Clark didn’t think much about the dime-sized, dark red spot — and he’d never seen a dermatologist.

“It wasn’t causing any discomfort and it didn’t grow or change shape,” he says. “When I asked my primary care doctor to take a look, he said it was nothing to worry about.” Two years later, his new primary care provider saw the mole and immediately sent him for a biopsy.

A talented musician, Clark soon discovered he had melanoma, a disease that strikes over 100,000 Americans each year. Surgeons cut out the diseased skin on his shin. But his stage of melanoma required additional treatment. Clark endured 32 radiation treatments. Then he went through isolated limb infusion, in which doctors isolate the limb from the rest of the body with a tourniquet and then flood the area with heated blood and high-dose chemotherapy. “The treatment is so toxic, you have to be hospitalized,” Clark says.

Throughout Clark’s treatment for advanced stage 3 melanoma, new lesions continued forming. Clark’s wife, fellow musician Sanda Schuldmann, thought there might be a solution. A fan of the pianist Martha Argerich, Schuldmann knew that Argerich had received a diagnosis of stage 4 melanoma that had spread to her lungs decades before. She also knew that doctors at John Wayne Cancer Institute in Santa Monica, California, had treated Argerich with something called intralesional therapy.

With intralesional therapies, doctors administer treatment by needle injection directly to the tumor to jump-start the immune system and possibly obliterate cancerous tumors throughout the body. The late Dr. Donald Morton was among the first to repurpose the anti-tuberculosis drug bacillus Calmette-Guerin (BCG) as a first-line intralesional therapy for late-stage melanoma, publishing astonishing results in Annals of Surgery in 1974. In the study of 151 patients, Morton and his colleagues found that directly injecting BCG into metastatic melanoma lesions limited to the skin produced a 90% regression of injected lesions and a 17% regression of lesions that were left untouched. What’s more, one-quarter of these patients remained disease free for one to six years. Since BCG is still not Food and Drug Administration (FDA)-approved for the treatment of melanoma, it can be difficult to find physicians who are familiar with using it in this way.

Schuldmann reached out to John Wayne Cancer Institute, where she connected with Dr. Mark Faries, who is now a professor of surgery and co-director of the melanoma program at Cedars-Sinai The Angeles Clinic and Research Institute. Faries, who trained under Morton at the National Institutes of Health, agreed to review Clark’s medical records. Within days, Clark learned he was a candidate for BCG intralesional therapy and began traveling to California weekly to receive the experimental treatments. After 15 to 20 BCG injections, Clark’s lesions were gone.

Once considered an incurable disease in its advanced form, melanoma has emerged as one of the cancers most responsive to immunotherapy. Immune checkpoint inhibitors have dramatically improved outcomes for patients with late-stage melanoma, with more than half of patients on combination Yervoy (ipilimumab)/Opdivo (nivolumab) still alive years after treatment. Unfortunately, the remaining half don’t respond to treatment, and some experience debilitating side effects that force them to discontinue immunotherapy.

“Intralesional therapies can help bridge this gap by modifying the tumor microenvironment in such a way that the immune system can recognize it as foreign and attack, but without the toxicities of systemic treatment,” says Dr. Lynn Schuchter, chief of the division of hematology/oncology at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia. The hope is that injecting these therapies at the tumor site will train the immune system to identify cancerous cells and launch a systemic and sustainable attack. For patients like Clark with late-stage disease that hasn’t metastasized to distant sites, intralesional therapy can produce durable remission.

INTRALESIONAL THERAPY EXPLAINED

Intralesional therapy is the oldest form of immunotherapy and dates back to the 1890s. In its early stages, intralesional therapy was made with neutralized, non-live bacteria and other stimulatory proteins without a clear understanding of the immune system. “More recently, we’ve learned why the immune system shuts down closer to the level of the tumor, and now we have drugs that can make the tumor visible to the immune system,” says Dr. Genevieve Boland, surgical director of the therapeutic intralesional program at Massachusetts General Hospital in Boston.

The goal of intralesional therapies is to attract the body’s killer T cells and draw them toward the tumor. In fact, one of the first approved immunotherapies for melanoma was the inflammatory cytokine interleukin-2 (IL-2) because cytokines attract T cells to tumors. Unfortunately, agents like IL-2 and BCG fell from favor because of systemic side effects and inconsistent results. Patients experienced significant toxicities ranging from anaphylaxis to changes in blood pressure and heart rate with IL-2.

“We’ve now learned that the immune system doesn’t work the same way that other drugs work,” Faries says. “There’s a sweet spot for how much stimulation you need to induce the desired effect.” And you can get there by using the tumor as a weapon against itself.

The idea behind intralesional therapy is to activate both innate and adaptive immunity to transform the patient’s tumor into a personalized vaccine. The innate immune system is ready to roll when faced with a threat. It automatically kicks in when a person cuts a finger, develops strep throat or needs to fight off the common cold. Adaptive immune cells need to be trained and activated to fight disease.

“These adaptive immune cells help create the right microenvironment for the fighter T cells to come in and do their job,” Boland says. And since doctors inject therapies directly into the tumor, they can deliver drugs safely and at a much higher dose than systemic drugs like checkpoint inhibitors.

USING VIRUSES TO ACTIVATE THE IMMUNE SYSTEM

Denis McGlynn of Camden-Wyoming, Delaware, received his first melanoma diagnosis in 2011 at 65 years of age. After multiple surgeries to treat the aggressive skin cancer, the married father of two and grandfather of five had his first experience with immunotherapy in June 2019. Within days of completing 13 months on Opdivo, McGlynn experienced debilitating side effects.

“I was lying on my back for five days because every joint in my body ached,” recalls McGlynn. The steroid medication prednisone instantly quieted his pain temporarily. Today, he still takes 6 milligrams of prednisone daily for the autoimmune effects.

To make matters more complicated, McGlynn continued to develop cancerous lesions on his scalp. That’s when his doctor suggested he visit Penn Medicine for intralesional treatments with an agent called T-VEC (talimogene laherparepvec). “I had multiple lesions, and the T-VEC injections took only five or six seconds each,” McGlynn says. “When I came back two weeks later, all of the lesions were either healing or gone.”

T-VEC is a genetically engineered herpes virus that obtained FDA approval in 2015 to treat patients with stage 3 or stage 4 melanoma who have injectable lesions but who are not eligible for surgery. Intralesional T-VEC works in these cases because it’s a modified virus, and research suggests viruses are among the best agents to reactivate a tumor’s microenvironment.

“The immune booster is attached to the virus and the virus has the ability to enter cells. When you inject this conjugate of the herpes virus with the immune booster into a melanoma nodule, it’s like raising a red flag and saying, ‘hey, immune system, here I am — attack me,’” Schuchter says.

Called an “oncolytic virus” because of its ability to selectively target, infect and annihilate tumor cells, T-VEC essentially trains the immune system to identify and attack the cancer not only in the injected tumor but also all tumors susceptible to the immune response — and in some cases, it produces complete responses.

“These oncolytic viruses rupture the tumor and kill cancerous cells while simultaneously stimulating the immune system,” Boland says. “We can create this superactive immune response locally, at the site of the tumor, while limiting or even eliminating the toxicities associated with traditional immunotherapy.”

In McGlynn’s case, the treatment was wildly successful. He hasn’t seen a lesion reappear since his last treatment in October 2020. Researchers are investigating other potential targets for melanoma, including other viral vectors, such as coxsackieviruses, HF-10, adenovirus, reovirus, echovirus and Newcastle disease virus. They’re also exploring another class of drugs to boost “innate immunity” — the immune system’s first responder cells that trigger T cells to kill tumors. Like viruses, these therapies activate the warning signs required for the immune system to launch an effective attack against a foreign invader. “Ideally, this sets off a strong reaction within the body that can turn an immunologically ‘cold’ tumor into a ‘hot’ one,” Boland says.

No matter which agents doctors choose, side effects of intralesional therapies tend to be minimal, particularly compared with systemic treatments. The most common complaints relate to soreness at the injection site and mild fatigue. However, a small subgroup of patients may develop inflammatory syndromes like those doctors see with checkpoint inhibitor therapy.

INTRALESIONAL THERAPY BEYOND THE SKIN

Down the line, combination treatment with intralesional therapy and checkpoint inhibitors may even play a role in the treatment of complicated tumors, such as stomach and pancreatic cancer. “The tumor microenvironment of pancreatic cancer has a lot of fibrous tissue, so the local tumor environment acts like a shield hiding the cancer from the immune system,” Schuchter says. “Using ultrasound guidance and other techniques, doctors can inject therapy directly into the tumor to help the immune system recognize cancerous cells and destroy them.”

Unfortunately, scientists don’t know yet who is most likely to respond to treatment. They don’t know whether it’s best to use intralesional therapies as a first-line approach or a last-ditch effort.

“Even though we inject T-VEC directly into tumors, it’s still a weakened form of the herpesvirus, and that makes it potentially dangerous,” Schuchter says. “Patients also have to cover the lesions for a week, and staff have to implement a variety of safe handling practices.”

Some clinics reserve a specific room for intralesional therapies and perform the procedure only at the end of the day. Others have strict preparation and cleaning requirements. And all intralesional therapies require consistent refrigeration. This level of preparation, time, training and logistics can be challenging or even impossible for community clinics.

“It’s important not to overhype intralesional therapy since it’s relevant for only a small subset of patients,” Schuchter says. But when it works — and sometimes it does work — patients reclaim their lives and enjoy decades-long survival. Innovations to this type of therapy with newer drugs are entering clinical trials.

“My one wish is that more people knew that intralesional therapy is an option,” Clark says. He is so indebted to BCG — he credits the drug with saving his life — that he partnered with a musicologist friend from his Peabody Institute days to develop a musical composition using notes B, C and G for Faries. “It’s probably the first fugue for a drug,” he says. Now that’s something to sing about.

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Immunotherapy for non-small cell lung cancer: A guide

Immunotherapy for non-small cell lung cancer: A guide

  • June 15, 2021

Immunotherapy is one of several treatment options for non-small cell lung cancer (NSCLC). A type of immunotherapeutic medication called immune checkpoint inhibitors teaches the body’s immune system to recognize and destroy cancer cells. It can have longer-lasting effects than other treatment options for NSCLC and can improve the outlook for people with the disease.

Immunotherapy is a new and emerging treatment option for cancer. Many of the first clinical trials on its effectiveness were initially published in 2015 or later.

Several studies have shown that immunotherapy can enhance overall survival for people with NSCLC. So the Food and Drug Administration (FDA) has approved several immune checkpoint inhibitors to help treat this condition.

This article will describe how doctors use immune checkpoint inhibitors to treat NSCLC. It will compare this treatment with chemotherapy and radiation therapy and explain what a person taking this medication can expect before and during treatment.

If a person is having immunotherapy, it means they are receiving medications that help their own immune system to find and destroy cancer cells.

The immune system protects the body against certain dangers, such as bacteria and fungi. But it does not always identify cancer cells as a danger. Immunotherapy teaches the body this difference, as well as how to fight these cancer cells. Scientists sometimes achieve this by introducing cells to the body that they have made or modified in a laboratory setting.

Sometimes, cancer cellscontain “messengers” that essentially shut down the immune system. Immunotherapy may also target these messengers, which keeps the immune system working at its best.

Some people visualize cancer cells as putting the “brakes” on immune system cells. Medications, such as immune checkpoint inhibitors that treat NSCLC, work to take the brakes off so the immune system can work better.

Immune checkpoint inhibitors are not effective in all people who have NSCLC. Some people are treatment-resistant, meaning the medications do not seem to help at all. Other people develop acquired treatment resistance. This means the medications work for a while, then stop working. A person should ask their doctor about how well they perceive the medication to be working.

There are several key similarities and differences between immunotherapy and other NSCLC treatments, such as chemotherapy and radiation therapy. These include their:

  • Function: Immunotherapy focuses on the entire immune response, teaching it to react more effectively to the presence of cancer cells. Chemotherapy kills cancercells directly but affects the whole body, too. Radiation therapy works by being directed to specific areas in the body to destroy cancerous cells.
  • Location: Immunotherapy is a systemic treatment for cancer. This means the approach affects the entire body instead of a specific tumor area. Chemotherapy is also systemic. Systemic cancer treatments are different from regional options such as radiation, which doctors aim directly at a specific area of cancer cells.
  • Effectiveness: Taking immunotherapy alone or in combination with other therapies, such as chemotherapy or radiation therapy, can significantly improve outcomes in people with lung cancer. Immunotherapy can provide long-term benefits because instead of attacking the cancer only while the treatment is in a person’s body, it teaches the body to fight the cancer. The body can remember this even once treatment has finished.
  • Side effects: Chemotherapy can attack healthy cells as well as cancerous ones, so a person can experience hair loss and nausea due to cell damage. Side effects from immunotherapy happen when the body overreacts to the treatment, or it receives it in the wrong place. Symptoms can range from mild to life threatening.

A doctor may prescribe immunotherapy treatments in combination with chemotherapy. As well as combining different immune checkpoint inhibitor types, this combination may help a person with NSCLC live longer, according to a 2019 article in the journal Clinical Cancer Research.

For example, a study published in the New England Journal of Medicine compared people with metastatic NSCLC receiving chemotherapy with people who received chemotherapy plus the immunotherapy pembrolizumab. After 12 months, the estimated overall rate of survival for the group who received both medications was 69.2% compared with 49.4% who took only chemotherapy.

Learn about the 10 most common side effects of chemotherapy here.

Doctors prescribe three main types of immune checkpoint inhibitors to treat NSCLC. These are:

  • PD-1 inhibitors: Programmed-death 1 (PD-1) is a protein naturally present in the body. The protein is on the surface of immune system cells known as T cells. These cells work to protect the body from infection and may have cancer-fighting properties. PD-1 inhibitors include the medications pembrolizumab and nivolumab.
  • PD-L1 inhibitors: Programed-death ligand-1 (PD-L1) is another protein type that some cancer cells commonly have. If PD-1 attaches to PD-L1, the PD-1 protein signals the PD-L1 cell to stop killing the cancer cell. PD-L1 inhibitors include the medications atezolizumab and durvalumab.
  • CTLA-4 inhibitors: Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitors boost the immune response by blocking the CTLA-4 proteins that exist on T cells. One example is ipilimumab. It can work alongside nivolumab and does not necessarily require chemotherapy.

Doctors prescribe PD-1 and PD-L1 inhibitors as immunotherapy fighters to enhance a person’s immune system. Doctors call these types immune checkpoint inhibitors. These medications help to ensure the immune system kills cancerous cells.

If a doctor thinks immunotherapy will work, a person will usually take the medications until their cancer progresses or the disease becomes too toxic. If they have an unanticipated side effect, they may also discontinue the medication.

Other types of immunotherapy for NSCLC include immune system modulators and therapeutic vaccines.

Learn more about these different types of immunotherapy for lung cancer here.

A doctor may perform biomarker testing before prescribing immunotherapy. This testing measures the likelihood of response to immunotherapy. Some tumors do not express PD-L1 proteins. When this is the case, prescribing the medications would likely be ineffective. Because these tests are not perfect predictors, some doctors may not use them.

A doctor will describe a person’s overall treatment plan to them. This should include:

  • an explanation of recommended medications
  • their anticipated side effects
  • how they will help to treat a person’s cancer

Learn about possible complications of lung cancer here.

The processes and side effects of immune checkpoint inhibitors for NSCLC will depend on which type of treatment a person receives.

Immunotherapy is a cancer treatment that may extend the life of those with NSCLC. The medication works to keep cancer cells from preventing immune system cells from killing them.

Because not all people are a good fit for immunotherapy and the medications may cause severe side effects, doctors will carefully evaluate if immunotherapy could benefit a person with NSCLC.

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Local hospital explains revolutionary CAR T-cell immunotherapy for cancer patients

  • June 13, 2021

SAN ANTONIO – There’s a breakthrough therapy for treating patients with blood cancer called CAR T-cell immunotherapy.

Dr. Paul Shaughnessy, medical director of the Adult Blood and Marrow STEM Cell Transplant Program at Methodist Hospital explains the therapy and how exactly it works.


How does it differ from other forms of cancer therapy?

“This immune therapy is much more directed, as much more specific to attack just the cancer cell and direct our immune system to fight cancer and our immune systems recognize and fight cancer all the time,” said Shaughnessy. “But this gives that extra boost to our immune cells to recognize this cancer that’s growing in the body unchecked and can really direct the immune system to fight cancer even more powerfully than chemotherapy.”


CAR T-cell immunotherapy

CAR T-cell immunotherapy is a new therapy that programs a patient’s immune system to recognize and fight cancer. The immune system is responsible for ridding the body of abnormal cells that are foreign (like cancer) or infected.

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T-lymphocytes (T-cells) are a type of cell responsible for killing abnormal cells. During the CAR T-cell treatment process, T-cells are drawn from a patient’s blood and genetically modified to recognize the patient’s cancer cells when reinfused.

Here’s how it works:

  • First, a patient’s white blood cells are collected through a process called apheresis.

  • Then, the T-cells are isolated from other blood cells.

  • T-cells are then modified in a special facility to program them to recognize the cancer cells, which can be thought of as “fighter” T-cells.

  • Lastly, the new “fighter” T-cells are re-infused into the patient to target and kill cancer.


Doris Franke, former educator and patient shared her experience receiving CAR T-cell immunotherapy after qualifying for the therapy after two unsuccessful cancer therapies.

“It meant the world to me gave me an opportunity to have a longer period of remission so that I can enjoy my family, my grandchildren, this beautiful world, all kinds of activities that I’m so grateful that I was chosen to be part of this trial,” said Franke. “It was like a miracle. After I received the treatment, I had a reaction when I was in the hospital for several weeks, I came out of that and I just started getting better. After that, I felt good. I gained back my energy.”

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Old antidepressants show promise as immuno-oncology treatments in melanoma and colon cancer

Old antidepressants show promise as immuno-oncology treatments in melanoma and colon cancer

  • June 12, 2021

A class of antidepressants known as monoamine oxidase inhibitors (MAOIs) first hit the market in the 1950s and has since been eclipsed by drugs that are less likely to cause unwanted side effects. Now, scientists at the University of California, Los Angeles (UCLA) have evidence that these drugs may be able to be repurposed in the treatment of cancer.

The UCLA researchers discovered MAOIs help the immune system fight cancer, slowing the growth of colon tumors and melanoma in mice. They reported their findings in two papers, one published Nature Communications and the other in Science Immunology, UCLA said in a statement.

By studying immune cells from melanoma tumors in mice, the UCLA team discovered that immune cells that had invaded the tumors showed high activity of the gene monoamine oxidase A. The protein that gene produces, MAO-A is the target of MAOI drugs.

Mice that didn’t produce MAO-A in tumors showed better control of melanoma and colon cancer. When the animals were treated with the MAOIs phenelzine, clorgyline or mocolobemide, tumor growth slowed. The treatment worked even better in combination with drugs that block the immune checkpoint PD-1, the researchers reported.

RELATED: Could immuno-oncology treatments get a boost from a 64-year-old antipsychotic?

So how to MAOIs fight cancer? The UCLA team discovered that by blocking MAO-A, the antidepressants boost the activity of the immune system’s T cells. The drugs also inhibit tumor-associated macrophages, which normally function to help tumors evade immune destruction.

In essence, then, MAO-A could be considered another immune checkpoint, the researchers suggested.

To back up that theory, the UCLA researchers measured MAOA gene expression in several types of tumors from patients. They discovered a link between high MAOA expression and shorter survival times.

The UCLA researchers noted the longstanding belief in the scientific community that there is cross-talk between the immune system and the nervous system. And this is not the first team to propose repurposing a brain treatment in cancer. Last year, for example, Australian researchers published a study showing that when they combined the antipsychotic prochlorperazine with a PD-L1 inhibitor in mice, it outperformed either therapy alone at shrinking tumors.

Researchers at the University of Southern California are running a phase 2 clinical trial of the MAOI phenelzine in prostate cancer patients. In interim results reported last year, they said that 11 of 20 participants saw their PSA levels drop after being treated with the antidepressant.

The UCLA researchers said they have patented the combination therapy they tested in mouse models of melanoma and colon cancer but have yet to try it in people. Still, they believe it’s an idea worth pursuing, especially because cancer patients are four times as prone to depression as the general population is.

“We suspect that repurposing MAOIs for cancer immunotherapy may provide patients with dual antidepressant and antitumor benefits,” said senior author Lili Yang, Ph.D., associate professor of microbiology, immunology and molecular genetics, in the statement.

Freiburg researchers receive ERC funding to develop and test immunostimulatory drug candidates

Macrophages can aid tumor growth by distracting cancer-killing CD8+ T cells

  • June 11, 2021

A Ludwig Cancer Research study adds to growing evidence that immune cells known as macrophages inhabiting the body cavities that house our vital organs can aid tumor growth by distracting the immune system’s cancer-killing CD8+ T cells.

Reported in the current issue of Cancer Cell and led by Ludwig investigators Taha Merghoub and Jedd Wolchok at Memorial Sloan Kettering (MSK) and Charles Rudin of MSK, the study shows that cavity-resident macrophages express high levels of Tim-4, a receptor for phosphatidylserine (PS), a molecule that they surprisingly found on the surface of highly activated, cytotoxic and proliferative CD8+ T-cells.

“We believe T-cells that infiltrate the peritoneal cavity can be distracted by the interaction with Tim-4-expressing macrophages,” explained study first author Andrew Chow, an assistant attending physician at the Ludwig Collaborative Laboratory at MSK.

The researchers also show that blocking Tim-4 in mouse models of cancer can prevent this distractive interaction and enhance the effectiveness of immunotherapies.

“I think in patients who have these serous cavity macrophages expressing high levels of Tim-4, blocking Tim-4 will make immune based therapies more effective,” Merghoub, co-director of the Ludwig Collaborative Laboratory at MSK, said.

Just as people living in different cities might have distinct customs or accents, the macrophages in our bodies can adopt specialized functions and respond to disease differently depending on which tissue they inhabit. Scientists are increasingly interested in such localized responses because macrophage activities can influence recovery from illness or injury and responses to therapy.

Merghoub, Wolchok, Rudin, Chow and colleagues began exploring the role of macrophages in tumor immunosuppression after noticing that cancer patients with lesions in their pleural and peritoneal cavities-;which house the lungs and organs of the gastrointestinal tract, respectively-;were substantially less responsive to immune checkpoint blockade therapy, which stimulates a CD8+ T cell attack on tumors.

“That told us there was something immunosuppressive in these cavities, so we went hunting for what that could be,” Chow said.

Previous studies have shown that other immunosuppressed sites in the body, such as the liver and bone, harbor macrophages expressing high levels of Tim-4. Others have shown that macrophages living in the pleural and peritoneal cavities of mice also exhibit a strong Tim-4 signal.

The researchers therefore suspected that cavity-resident macrophages might impair the anti-tumor activity of CD8+ T cells through the actions of Tim-4.

These suspicions were partly vindicated when the researchers analyzed the cavity macrophages of human lung cancer patients and found that while Tim-4 levels varied between individuals, those with higher levels of the receptor tended to have a reduced presence of CD8+ T cells that had features of responding to the tumor.

Based on these observations, the researchers explored whether blocking Tim-4 would enhance the efficacy of PD-1 blockade therapies in a pre-clinical mouse model of colon and lung cancer in the peritoneal cavity.

“We showed that you get the best tumor protection when you block both molecules,” Chow said.

While blocking Tim-4 alone didn’t reduce the number of tumors or improve survival in the mice, it did enhance the tumor protection afforded by PD-1 blockade and boost the numbers of CD8+ T cells in the peritoneal cavity. The researchers also showed that Tim-4 blockade reduces immunosuppression in adoptive T-cell therapy, in which tumor-targeting T-cells are isolated and selectively grown in a lab before they’re reinfused into the patient.

“Together, these results suggest that Tim-4 blockade is a strategy to improve immunotherapy, regardless of whether you’re trying to boost your immune response through immune checkpoint blockade therapy or via adoptive T-cell therapy,” said Chow.

For Merghoub, the new findings demonstrate the need to better understand the diversity of immune landscapes in and around tumors. “In the same way we profile tumor genomes to guide the use of small molecule inhibitors for targeted therapies, we need to profile the immune landscapes of tumors and personalize immune-based therapies on the basis of such studies,” he said.

ASCO: Alpine reports 61% 'clinical benefit' in early trial of CD28-targeted immuno-oncology drug

ASCO: Alpine reports 61% ‘clinical benefit’ in early trial of CD28-targeted immuno-oncology drug

  • June 7, 2021

Alpine Immune Sciences turned heads a year ago when AbbVie formed a deal with the company worth up to $805 million in milestone payments for a first-in-class lupus drug that inhibits a protein on the immune system’s T cells called CD28. But the company is also pursuing one strategy for stimulating CD28 to improve the immune response to cancer—and it has early evidence its plan may be working.

Alpine presented initial data from an ongoing phase 1 trial of its immuno-oncology candidate ALPN-202, a CD28 costimulator, during the American Society of Clinical Oncology (ASCO) virtual annual meeting. The treatment was well tolerated, Alpine said, and 61% of the 23 patients who were able to be evaluated derived some clinical benefit, which the company defined as stable disease or better.

By binding CD28, ALPN-202 primes T cells for activation. The drug also binds to and antagonizes the immune checkpoints CTLA-4 and PD-L1, freeing up the immune system to attack cancer, the company explained during the ASCO presentation.

The 32 participants in Alpine’s phase 1 study of ALPN-202 have a variety of tumor types, including pancreatic, colorectal and uterine cancers. The patients had “generally received many prior lines of therapy” before enrolling in the trial, though few had received immunotherapy, said Stanford Peng, M.D. Ph.D., president and head of R&D at Alpine, during the ASCO presentation.

The company’s analysis of the patients in the trial found several markers of immune stimulation, including a proliferation of beneficial memory T cells and downregulation of regulatory T cells, which can suppress immune activity.

“Most of the participants enrolled in the study had tumors traditionally considered unresponsive to immunotherapy,” Peng said. “Nonetheless, evidence of clinical benefit appears to be present at this early stage.”

RELATED: AbbVie spends $60M, with $805M in biobucks, for Alpine Immune’s lupus asset

Alpine is not the only company pursuing CD28-targeted therapies in immuno-oncology. Regeneron is working on several CD28 costimulatory bispecific antibodies, which it has explored in combination with its PD-1 inhibitor Libtayo. Last year, Regeneron reported 70.8% survival in a mouse model of colon cancer for a bispecific targeting PSMA and CD28 combined with PD-1 blockade. That was a significant improvement over either the bispecific or the anti-PD-1 drug alone.

Targeting CD28 has proven challenging, however, because of safety concerns. Some patients in early clinical trials suffered the severe inflammatory reaction cytokine release syndrome, prompting developers to shelve CD28-targeted drugs.

Alpine said during ASCO that none of the participants in its phase 1 trial experienced cytokine release syndrome. Half of participants did have side effects, most of which were skin conditions such as rashes, the company said.

The phase 1 study will continue for the rest of the year, after which Alpine will choose the tumor types to be included for further study in an expansion trial. The company is also planning to launch a trial of the drug in combination with a PD-1 inhibitor, Peng said.

Immunotherapy for Small Cell Lung Cancer: Does It Work?

Immunotherapy for Small Cell Lung Cancer: Does It Work?

  • June 2, 2021

Small cell lung cancer (SCLC) is one of the two major categories of lung cancer along with non-small cell lung cancer (NSCLC).

SCLC makes up about 13 to 15 percent of all lung cancers. Smoking is thought to cause 85 percent of lung cancers and is strongly associated with SCLC.

Chemotherapy and radiation therapy are the most commonly used methods to treat SCLC.

But immunotherapy is a relatively new and promising treatment for SCLC and other cancers. It may also be combined with chemotherapy or radiation therapy as an initial treatment or used later if other therapies aren’t effective.

Read on to learn how immunotherapy works for treating SCLC and what the latest research says.

Immunotherapy involves taking medications that stimulate your immune system to identify and destroy cancer cells. Three primary classes of immunotherapy drugs are used to treat SCLC.

Immune checkpoint inhibitors

Your immune system undergoes a process called cancer immune surveillance. This means that your immune system searches for proteins called antigens produced by cancer cells. When it finds these antigens, your immune system targets the cancer cell and destroys it.

Your immune system uses certain proteins called checkpoints to turn your immune response on and off. These checkpoints help prevent your immune system from being too aggressive. But if checkpoints are overactive, they can prevent your immune system from identifying and targeting cancer cells.

Some tumors can go undetected by your immune system when these checkpoints are overactive, interfering with your T cells and natural killer cells’ ability to recognize cancer cells.

A class of immunotherapy drugs called immune checkpoint inhibitors block these checkpoints so your body can better recognize and kill cancer cells.

Tumor vaccines

Tumor vaccines are different from vaccines that target viruses. These vaccines bind to antigens produced in tumor cells, alerting your immune system to attack the cancer cells.

Monoclonal antibodies

Monoclonal antibodies are proteins made in a lab that act like your immune system’s antibodies. Antibodies are proteins produced by your immune system that bind to antigens attached to foreign substances in the body. This give your immune system the signal to attack them.

Cancer researchers can now design antibodies that target certain antigens found on cancer cells. This can help stimulate your immune system to kill cancer cells.

Chemotherapy and radiation therapy are the primary treatments for SCLC. But researchers are hopeful that immunotherapy can help improve the outlook for people with SCLC.

Little research is available on the effectiveness of immunotherapy as the sole, first-line treatment for SCLC. Since SCLC tends to be aggressive, the risk for complications is higher if chemotherapy isn’t administered as soon as possible.

Immunotherapy research is still relatively new, so there’s a lot that researchers don’t know. But dozens of clinical trials are currently examining the potential benefits of immunotherapy.

The majority of clinical trials have examined the combined effect of immunotherapy with chemotherapy. Studies have found mixed results about the effectiveness of immunotherapy:

  • In an older 2013 phase II clinical study, participants with extensive-stage SCLC were either given chemotherapy and a placebo or chemotherapy and a monoclonal antibody called ipilimumab. The researchers found only a minimal benefit of ipilimumab compared to a placebo.
  • A 2016 phase III clinical trial failed to find a benefit for overall survival with extensive-stage SCLC when combining ipilimumab with chemotherapy compared to chemotherapy and a placebo.
  • A 2018 phase III clinical trial examined the effect of the monoclonal antibody atezolizumab combined with chemotherapy in extensive-stage SCLC. The researchers found that atezolizumab increased overall survival compared to a placebo by 2 months.
  • A 2019 phase III clinical trial examined the potential benefit of the immunotherapy drug durvalumab plus chemotherapy as a first-line treatment for people with SCLC that had spread to other parts of their body. The researchers found a significant improvement in overall survival in participants who received durvalumab compared to participants in the control group.

You can find the latest list of clinical trials that are actively recruiting participants in the United States by visiting the U.S. National Library of Medicine website and searching for keywords like “immunotherapy” and “small cell lung cancer.” The exact number of trials can vary over time.

Most clinical trials are examining the effectiveness of immunotherapy in combination with chemotherapy. Some specific drugs being investigated are:

  • ipilimumab
  • nivolumab
  • durvalumab
  • atezolizumab
  • pembrolizumab
  • M7824

If you have SCLC, you may be able to find clinical trials in your area that you can participate in. Government agencies, universities, and drug companies all run clinical trials.

Researchers have yet to determine how best to use immunotherapy to treat SCLC.

It may be used for people in the early stages of the disease in combination with chemotherapy, but may also be used in later stages if you don’t respond to initial treatments.

It’s not entirely clear who makes the best candidate for SCLC. But in general, people with autoimmune conditions or chronic infections may not make good candidates due to the risk of making the immune system overly active.

According to the American Cancer Society, immunotherapy can lead to one or more of the following side effects:

You can also experience a reaction after receiving immunotherapy drugs that can include symptoms like:

Immunotherapy can also lead to autoimmune reactions. This happens when the immune system attacks parts of your own body. In some cases, autoimmune reactions can severely damage vital organs and be life threatening.

Talk with a healthcare professional as soon as possible if you experience any concerning symptoms like those listed above.

SCLC tends to be aggressive. About 70 percent of cases aren’t diagnosed until it has already spread throughout the body.

It’s not currently clear how effective immunotherapy is for treating SCLC. Most research has examined immunotherapy combined with chemotherapy, and results have been mixed.

Dozens of clinical trials are currently being run in the United States and worldwide to examine how immunotherapy may help people with SCLC. Many are accepting volunteers to help better understand the relationship between immunotherapy and the prognosis of SCLC.

Common cold can help boost COVID-19 immunity

Common cold can help boost COVID-19 immunity

  • May 28, 2021

A team from QIMR Berghofer Medical Research Institute, in collaboration with La Trobe University, The University of Queensland, and Monash University, has found exposure to a common cold virus may help prepare the body’s immune system to respond to SARS-CoV-2.

The study is one of the first to demonstrate how the body’s ‘killer’ T cells, which specialise in killing infected cells, could use their memory of fighting other coronaviruses to respond more quickly to SARS-CoV-2 – the coronavirus that causes COVID-19.

Joint-lead researcher Associate Professor Corey Smith, who heads QIMR Berghofer’s Translational and Human Immunology Group, said the team found this response occurred in people who had previously recovered from a strain of the common cold, called the beta coronavirus, even though they had never before been exposed to the COVID-19-causing virus.

“T cells are the immune cells that recognise and destroy cells infected with SARS-CoV-2. They typically mount an early response, even before the body starts to produce antibodies.

“Most importantly, T cells develop a lasting memory of viral infections, which enables the immune system to respond rapidly in the event of reinfection,” Associate Professor Smith said.

“This study confirms there is T cell cross-recognition of this beta coronavirus, which causes the common cold, and of SARS-CoV-2. We hope this significant finding will have implications for global understanding of how our immune system’s memory might be harnessed to tackle COVID-19-diseased cells.”

Co-lead researcher Professor Stephanie Gras, from the La Trobe Institute for Molecular Science, said the research findings will also help scientists better understand how immune cells recognise newly emerging SARS-CoV-2 variants.

“We are the first to demonstrate the similarities in chemical structure between both the SARS-CoV-2 and beta-coronavirus strains and how this results in the ability of killer T cells to recognise and respond to both,” Professor Gras said.

“A lot of headway is being made in the battle against COVID-19 with vaccine rollouts currently underway, but the ongoing emergence of new variants has highlighted the importance of continuing to identify new ways of targeting this disease.”

QIMR Berghofer researcher Dr Katie Lineburg said the team studied blood from 37 recovered COVID-19 patients to understand the biology behind why some people have better T cell immunity to the virus than others.

“Initially we looked at the T cell responses in a larger group of people shortly after they recovered from COVID-19 and identified that a majority of them showed a strong immune response to a specific portion of the SARS-CoV-2 virus called the nucleocapsid protein,” Dr Lineburg said.

“We were able to show that because the genetic sequence of this nucleocapsid protein is very similar between SARS-CoV-2 and a common beta coronavirus, the memory T cells targeting each virus are also capable of recognising the other and producing the molecules needed to kill an infected cell.

“We’re hopeful that identifying which parts of the virus trigger an immune response will help us to develop a T cell immunotherapy that could be used to treat patients who don’t respond well to existing treatments.”

/Public Release. This material comes from the originating organization and may be of a point-in-time nature, edited for clarity, style and length. View in full here.

Immunotherapy for breast cancer: Types and effectiveness

Immunotherapy for breast cancer: Types and effectiveness

  • May 28, 2021

Immunotherapy is a treatment option for some types of breast cancer. It uses medications to stimulate the immune system to destroy cancer cells.

Immunotherapy drugs work with an individual’s immune system to help it recognize and attack breast cancer cells. Doctors may use immunotherapy by itself or in combination with chemotherapy, radiation therapy, or other treatments.

This article looks at the currently available immunotherapy treatments in more detail, including how they work and which types of breast cancer they may treat.

Immunotherapy is a treatment method for some types of breast cancer. It uses drugs that stimulate the immune system to identify and destroy cancer cells. These medications include immunomodulators and targeted antibodies.

Cells in the body contain proteins called immune checkpoints. These immune system regulators signal that cells are healthy.

Immune checkpoints allow the immune system to fight infected or diseased cells while preventing it from attacking healthy tissues.

The immune system is complex and involves different types of cells, including T cells, which circulate the body checking for disease or infection. These specialized cells examine other cells to identify immune checkpoints.

If the immune system does not recognize proteins within cells, it attacks them. This process is essential in allowing the body to fight diseases and infections.

Sometimes, the immune system does not fight off breast cancer cells effectively. There are two main reasons for this.

Firstly, precancerous or early cancerous cells are similar to healthy cells. The immune system may not recognize them as harmful until breast cancer develops further. Secondly, as cancerous cells develop, they can change genetically to prevent the immune system from detecting them and identifying them as harmful. Cancer cells can also grow and multiply quickly, which can overwhelm the immune system.

Immunotherapy drugs can help support the immune system to destroy cancer cells. Doctors may prescribe various options, depending on the type of breast cancer.

Immunomodulators

Cancer cells can contain immune checkpoints that prevent the immune system from attacking them.

PD-1 and PD-L1 are two types of immune checkpoint proteins. T cells contain PD-1, and healthy cells contain PD-L1. These proteins bind, which prevents T cells from destroying healthy cells.

Cancer cells can contain PD-L1, which prevents T cells from destroying them. Immune checkpoint inhibitors stop PD-1 from binding to PD-L1, which allows T cells to kill cancer cells.

Immune checkpoint inhibitors are drugs that block immune checkpoints on cancerous cells or the T cells that see them as healthy. The immune system can then identify the cells as harmful and attack them.

Targeted antibodies

Immune targeted therapies, or targeted antibodies, recognize specific markers on cancer cells and stop these cells from growing.

Other targeted therapies work in the same way as the body’s natural antibodies and help the immune system recognize cancer cells as harmful.

People may also use immunotherapy in combination with other treatments, such as chemotherapy, to target cancer cells.

Vaccines

Although the Food and Drug Administration (FDA) has not yet approved any vaccines for breast cancer treatment, research is ongoing.

The type and stage of breast cancer will determine what type of immunotherapy a person receives.

Immunomodulators

There are currently two FDA-approved immune checkpoint inhibitors: Tecentriq (atezolizumab) and Keytruda (pembrolizumab).

Tecentriq

Tecentriq inhibits PD-L1 proteins, and doctors may use it to treat:

  • metastatic triple-negative breast cancer (TNBC)
  • PD-L1-positive breast cancer
  • locally advanced breast cancer where surgery is not effective

Doctors may use Tecentriq alongside a chemotherapy drug called Abraxane (albumin-bound or nab-paclitaxel) to target advanced triple-negative breast cancer.

Keytruda

Keytruda inhibits PD-1 proteins. Doctors may use Keytruda alongside chemotherapy to target triple-negative breast cancer that has spread to other areas of the body or has returned locally and is not treatable with surgery.

Targeted antibodies

Targeted antibodies include:

  • Perjeta (pertuzumab): For HER2-positive breast cancer.
  • Trodelvy (sacituzumab govitecan): For triple-negative breast cancer.
  • Herceptin (trastuzumab): For HER2-positive breast cancer.
  • Enhertu (trastuzumab deruxtecan): For advanced HER2-positive breast cancer.
  • Kadcyla (trastuzumab emtansine): For HER2-positive breast cancer.

The American Cancer Society states that people taking Tecentriq will need to receive it intravenously every 2 weeks. Those on Keytruda will receive it intravenously every 3–6 weeks.

Currently, there is no clear time frame for how long immunotherapy may take to work. More research is necessary to confirm the ideal duration of treatment.

Doctors may give targeted antibodies as a single injection or as a course of injections spanning several months. In some cases, they may use this treatment alongside chemotherapy.

According to the Cancer Research Institute (CRI), HER2-directed immunotherapy treatment is highly effective. However, only about 20% of people who have high levels of HER2 expression respond to this type of treatment.

Even with treatment, HER2-positive breast cancer can progress or recur, creating the need for other treatment methods.

Researchers are testing immunotherapy with chemotherapy. In a 2018 study, researchers trialed adding Tecentriq to nab-paclitaxel in people with metastatic TNBC who had not previously received treatment for this cancer. They found that some of the participants did benefit from this combination, but others had to discontinue the treatment due to side effects. In March 2019, the FDA approved this treatment combination.

Experts believe that a combination of immunotherapy treatments, such as using a vaccine alongside monoclonal antibodies or chemotherapy, may be more effective in stimulating an immune response.

Immunotherapy drugs may cause side effects, which can include:

In some cases, more serious side effects can occur, although these are less common.

Some people may have an infusion reaction when taking drugs intravenously. The symptoms are similar to those of an allergic reaction and can include:

  • fever
  • chills
  • facial flushing
  • a rash
  • itching
  • dizziness
  • wheezing
  • difficulty breathing

Immunotherapy removes some of the protection against healthy cells. Without this protection, the individual may experience an autoimmune reaction, meaning that the immune system mistakenly attacks healthy tissues. Corticosteroids can help suppress the immune system and reduce potential autoimmune reactions.

If people experience any side effects from immunotherapy drugs, they should let their healthcare team know immediately. If the side effects are severe, a person may have to stop the treatment.

Immunotherapy drugs are relatively new treatments, and research is ongoing to confirm how best to use them. If people want to learn about immunotherapy treatment for breast cancer, they can talk with their healthcare team about local clinical trial options.

The CRI states that current FDA-approved immunotherapy treatments are unlikely to cure advanced breast cancer. However, researchers are currently studying new immunotherapy treatments, many of which are producing promising results. People with advanced breast cancer may, therefore, wish to consider taking part in clinical trials exploring newer treatment options.

The CRI has a database where people can search for clinical trials that are currently enrolling participants.

Immunotherapy is a relatively new treatment method for cancer that stimulates the immune system to attack cancer cells. It can effectively treat some types of breast cancer.

Whether immunotherapy is successful for an individual depends on doctors finding the best approach for the type and stage of cancer. Immunotherapy may work better if doctors combine it with other treatments.

These therapies are relatively new, and research into their use is ongoing. If people want to find out about current clinical trials using immunotherapy for breast cancer treatment, they can discuss the options with their healthcare team or directly search for trials using the National Library of Medicine’s clinical trials database.

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