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Diffuse Large B-Cell Lymphoma Immunotherapies and the Emergence of Bispecific Antibodies

The immune system is often ‘out-smarted’ in cancer. Cancer cells have evolved many ways to evade detection by the immune system, including genetic changes that make them less recognizable to immunomodulatory cells and expression of proteins that dampen the immune system (1). Immunotherapy – a type of biological therapy that helps the immune system detect and destroy cancer cells – is an up and coming effort to mount an offensive response to tumor immune evasion. There are several different types of immunotherapy that are approved or being tested in a variety of cancers, including immune checkpoint inhibitors, T-cell transfer therapy, monoclonal and bispecific antibodies, treatment vaccines, and immune system modulators, with certain immunotherapies more developed than others, and other cancer therapies (i.e. chemotherapy, radiation, surgery) still being the more widely used option. Given this, many immunotherapies are offered in the 2nd or 3rd line. Here, we will briefly summarize the advancement of 2nd/3rd line immune treatment options for Diffused Large B-Cell Lymphoma (DLBCL).

CAR T-Cell Therapy in DLBCL

DLBCL is an aggressive type of non-Hodgkin lymphoma (NHL) that affects B-cells, or the cells that are crucial for antibody production to fight infections. More than 18,000 people in the United States are diagnosed with DLBCL each year (2), and the standard 1st line for these patients is chemotherapy (3). In instances of treating relapsed/refractory DLBCL, while further chemotherapy combination regimens are available, the success of chimeric antigen receptor (CAR) T-cell therapy in this disease space makes this is a widely used option. In CAR T-cell therapies, T-cells isolated from the patients blood are modified to express a CAR specific to a cancer cell antigen, and are then given back to the patient (4). Providing T-cells with the right receptors to recognize cancer cells helps them detect and destroy the cancer cells. In the case of R/R DLBCL, the approved CAR T-cell therapies are Axicabtagene Ciloeucel (Yescarta), Lisocabtagene Maraleucel (Breyanzi), and Tisagenlecleucel (Kymriah). All 3 therapies have similar efficacy profiles – having the ability to achieve lasting remissions in 40-50% of patients who relapse after 2 lines of conventional therapy (5). However, the 50-60% of patients who fail on CAR T-cell therapy cannot be overlooked, and new treatment options need to be available for patients who relapse after 2 lines of conventional therapy and/or relapse after CAR-T cell failure.

Bispecific Antibodies in Diffuse Large B-Cell Lymphoma

Bispecific antibodies are emerging as a promising therapy for DLBCL. Bispecific antibodies are designed to bind both a tumor specific antigen (in the case of DLBLC, CD20) and an immune effector cell antigen (i.e. CD3) (6). Once the bispecific antibody binds the tumor antigen, then the also bound effector T-cell is activated for cytotoxic activity (7). There are currently several bispecific therapies under investigation for DLBCL, including Epcoritamab, Glofitimab, and Odronextamab. Ongoing clinical trials are testing the efficacy and safety profiles of these bispecific antibodies in R/R NHL patients after 1-2 prior therapies, and they are achieving clinical response rates, such as progression-free survival of 46%, 57% and 60%, respectively, with the most common adverse event being cytokine release syndrome (8,9,10). Importantly, in the phase 1 study of Odronextamab, the study is investigating the anti-tumor activity post CAR T-cell therapy. Current data suggests that 8/24 patients post CAR T-cell therapy achieved an overall response, with 5/24 reaching complete response (10). Therefore, bispecific antibodies may be promising 2nd or 3rd line therapies in DLBCL.

Conclusion

It is unclear how many physicians are aware of the ongoing clinical trial data for bispecific antibodies in DLBCL and what their willingness is to try these therapies is. Furthermore, it remains in question where bispecific antibodies will fall in the course of treatment for DLBCL patients. For example, are they a promising therapy post CAR T-cell failure, or will they become standard of care post relapse/refractory to chemotherapy? It will be imperative to follow the course of ongoing clinical trials to better understand how different immunotherapies will shape cancer treatment.

About the author:

Lindsay Gurska is a Cell Biology PhD trainee at Albert Einstein College of Medicine. She is interested in pursuing a career in science communication. Her current interest is in writing and creating promotional content for the therapeutic landscape.

References

  1. https://www.cancer.gov/about-cancer/treatment/types/immunotherapy
  2. https://lymphoma.org/aboutlymphoma/nhl/dlbcl/relapseddlbcl/
  3. NCCN guidelines
  4. https://www.cancer.org/treatment/treatments-and-side-effects/treatment-types/immunotherapy/car-t-cell1.html
  5. https://lymphomahub.com/medical-information/why-patients-with-large-b-cell-lymphoma-fail-car-t-therapy-and-how-to-manage-them
  6. Lum LG, Thakur A. BioDrugs. 2011;25(6):365-379
  7. Baeuerle, P and Reinhardt, C. Cancer Research. 2009;69(12):4941–4
  8. Clausen MR, et al. Journal of Clinical Oncology. 2021;39 (Supplement 15): 7518. Presented at ASCO 2021, Abstract #7518
  9. Carlo-Stella, et al. Presented at EHA 2021, Abstract#EP501
  10. Bannerji R, et al. 2020;136 (Supplement_1) 42-43. Presented at ASH 2020, Abstract#400
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