Immunotherapies continue to be a ‘revolution’
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In 2016, the FDA approved the first immunotherapy for lymphoma. Since then, the field has exploded and now, just 4 years later, there are nine FDA-approved immunotherapy options for lymphoma, according to the Cancer Research Institute.
The most exciting classes of immunotherapies are chimeric antigen receptor T cell (CAR T-cell) therapies, immune checkpoint inhibitors, bispecific antibodies and vaccines. Currently, new immunotherapies are being tested in lymphoma clinical trials and several have shown promising results.
“Immunotherapy has been a revolution in oncology overall. When we take a broader look, it's been a huge impact to lymphoma for even longer than the past 5 and 10 years,” Joshua Brody, MD, director of the lymphoma immunotherapy program at Tisch Cancer Institute at Mount Sinai and a HemOnc Today Next Gen Innovator, said in an interview.
The successful development of immunotherapy for lymphoma began more than 20 years ago with FDA-approved rituximab, a monoclonal antibody, according to a review published in Cancer & Biology Medicine.
“Rituximab for patients with low-grade, intermediate, and other grade B cell-derived, non-Hodgkin lymphomas, is central therapy and has been for a long time now, and optimization and improvement of monoclonal antibodies is still part of cutting-edge research,” Brody told Healio.
CAR T-cell therapy
CAR T-cell therapy represents one of the most promising options for patients with relapsed/refractory lymphomas. Currently, the existing research most strongly supports CAR T-cell therapy that targets CD19 for the treatment of lymphoma.
Results from ZUMA-1, the first multicenter phase 2 study of CAR CD19 T cells in diffuse large B-cell lymphoma, showed an overall response rate of 71%, and a complete response rate of 38% at 1 month. Also, results from the phase 2 JULIET trial indicated that treatment with CAR T-cell therapy led to durable responses among highly pretreated patients with relapsed/refractory DLBCL.
Combining CAR T-cell therapies with other immunotherapeutic approaches, like checkpoint inhibitors, may also benefit lymphoma patients; however, more research is needed.
So far, CAR T-cell therapies have only been studied in patients with relapsed/refractory disease, usually after failure of ASCT, according to the Cancer & Biology Medicine review. CAR T-cell therapies that target other molecules – such as CD20, CD22, CD30 and CD79a – are currently being studied to determine their efficacy in other lymphoma subtypes.
Checkpoint inhibitors
Cytotoxic T-lymphocyte associated protein 4 (CTLA-4), programmed cell death 1 (PD-1) and its ligand PD-L1 represent the most well-studied co-inhibitory ligands-receptors, researchers wrote in Cancer & Biology Medicine.
Pembrolizumab and nivolumab, anti-PD-1 monoclonal antibodies, have demonstrated efficacy in Hodgkin lymphoma, both alone and in combination with other treatments.
In the KEYNOTE-013 trial, researchers found that pembrolizumab demonstrated considerable clinical benefit in heavily pretreated patients with classical Hodgkin lymphoma. Further, recent research showed that pembrolizumab was associated with high response rates, durable activity and manageable toxicity among patients with relapsed or refractory primary mediastinal large B-cell lymphoma.
Results of the phase 2 CheckMate 436 trial revealed that nivolumab in combination with the antibody-drug conjugate medication brentuximab vedotin appeared safe and induced high antitumor activity among patients with relapsed or refractory primary mediastinal B-cell lymphoma. Also, nivolumab plus brentuximab vedotin appeared tolerable and safe among patients with relapsed or refractory Hodgkin lymphoma, according to phase 1/phase 2 data.
Combining brentuximab vedotin with chemotherapy may also be an option for patients with T-cell lymphoma.
“We have ECHELON-2 trial results showing overall survival benefit combining anti-CD30 antibody drug conjugate brentuximab with standard chemo, but the trial emphasized patients with anaplastic large cell lymphoma (ALCL), so we're not sure if we're really helping all T-cell lymphoma patients,” Brody said. “Certainly, for the patients with higher expression of these CD30 it's a reasonable extrapolation to say that we may help them with brentuximab plus chemo, but the absolute evidence was really there for ALCL. For all the other types of T cell lymphoma, there’s still a lot of improvement needed.”
As for newer research, anti-PD-1 therapy following treatment with CAR-T cell therapy showed efficacy in a small sample of patients with relapsed/refractory Hodgkin lymphoma, according to study data presented at the latest ASH Annual Meeting and Exposition.
Bispecific antibodies
The use of bispecific antibodies is one of the most promising and exciting advances in lymphoma, according to Brody.
Blinatumomab, an FDA-approved bispecific antibody primarily for ALL that has been around for many years, has been a little difficult to use in the treatment of certain types of B-cell non-Hodgkin lymphomas, Brody said. However, there are now some data on newer bispecific antibodies.
“These are antibodies that bind CD3 with one arm, CD20 with the other arm, [bringing] the T-cell near to the lymphoma cell and [activating] the T cell concurrently, so the T cell can hopefully start killing those lymphoma cells,” Brody told Healio. “The data are, I would say, the most exciting thing in low-grade and some intermediate-grade lymphomas over the past year or 2.”
Mosunetuzumab, one such T-cell bispecific antibody, has recently been shown to induce remissions in aggressive relapsed or refractory non-Hodgkin lymphoma after failure of CAR-T therapy at ASH 2019.
According to Brody, the data on bispecific antibodies indicate high response, partial and complete remission rates – some of which seem to be very durable – and overall good safety, though the toxicities are “not nothing.” Brody explained that individuals usually receive the first cycle of these therapies as an inpatient to ensure that they are well-tolerated.
Brody thinks a few bispecific antibodies will be FDA approved within the next year.
“But those are still, in some ways, generation 1.0 approaches, where we have a lot of advances to make on bispecific therapies, [like] how best to combine them with other therapies and how to make them as safe as possible,” he said. “So, lots of information still on how to improve and optimize efficacy and safety with bispecifics, but already incredibly exciting data, with high efficacy in patients for whom chemotherapy and other standard therapies have been ineffective.”
Vaccines
Along with bispecific antibodies, checkpoint inhibitors and CAR-T cells, the Lymphoma Immunotherapy Program at Mount Sinai and other groups are currently studying therapeutic vaccines for lymphoma, according to Brody.
“In contrast to preventive vaccines (like polio or measles vaccines), therapeutic vaccines treat cancer after it has developed by teaching each patients’ immune system how to specifically recognize and eliminate their own cancer cells,” Brody said. “One promising approach here is to inject immune stimulants directly into one tumor site, which can teach patients’ CD8 T cells to recognize cancer and then travel throughout the body to induce tumor regressions systemically.”
In a study published in Nature Medicine, Brody and colleagues described early results of this type of in situ vaccination. The data showed that recruiting and activating intratumoral, cross-priming dendritic cells is crucial to anti-tumor T cell responses and PD1-blockade efficacy. This type of situ vaccination are now being combined with anti-PD1 antibodies to treat lymphoma, breast cancer and head/neck cancers (NCT03789097), Brody said.
Future research
More progress has been made in lymphoma than any other type of cancer in terms of understanding the biology and pathophysiology of these diseases and regarding turning that understanding into actionable therapies over the last 20 years, according to Brody. However, there are subtypes of lymphoma where the progress has been poor that require more attention, especially all subtypes of T-cell lymphomas.
“Peripheral T cell lymphoma not otherwise specified is the greatest subset of these. These patients, a majority of them have poor outcomes,” Brody said. “With old fashioned CHOP-based chemotherapy, we help a few patients, but the majority have poor outcomes. We need to improve on those.”
Brody discussed the potential of using more thoughtfully engineered, gene-edited CAR T-cells for T-cell lymphomas; however, these are not “low hanging fruit.”
“Now this is a little weird because we have a T cell disease, and we're going to use another T cell to kill it. That's tricky. If the CAR T-cell is going after a T-cell target, won't the CAR T cells kill the CAR T cells? We have to avoid this thing called fratricide – killing of your brothers,” Brody said. “We can use some pretty fancy genetic engineering to go after one target that will be on the T-cell lymphoma – it could be CD7, it could be other things – and we can remove that target with CRISPR, otherwise gene editing those CAR T cells so they no longer have that target.”
This approach has some positive preclinical evidence and early phase clinical trials have begun, Brody added.
“T-cell lymphoma should be addressable with CAR T-cells and other immunotherapies. Even if that's a moonshot, we need to be taking big swings for this disease that's really had very little progress over the past 20 years, despite a few FDA approvals, HDAC inhibitors, pralatrexate, et cetera,” he said. “Still, the outcome for patients are poor, so we need to be thinking of brave, new and mechanistically distinct approaches to attack T cell lymphoma.” – by Savannah Demko
References
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- Cancer Research Institute. Immunotherapy for lymphoma.
- https://www.cancerresearch.org/immunotherapy/cancer-types/lymphoma. Accessed on Feb. 12, 2020.
- Herrera AF, et al. Abstract 649. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
- Heyman B, Yang Y. Cancer Biol Med. 2018;doi:10.20892/j.issn.2095-3941.2018.0037.
- Moskowitz CW. Abstract 290. Presented at: ASH Annual Meeting and Exhibition; Dec. 6-9, 2014; San Francisco.
- Neelapu S, et al. Abstract LBA-6. Presented at: The ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.
- Schuster SJ, et al. Abstract 6. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
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