Science Spotlight

Diffuse large B cell lymphoma gets new first line therapy

From the Gopal laboratory, Clinical Research Division, and the Smith laboratory, University of Washington Medical Oncology

Programmed death ligand 1 (PD-L1) is an immune checkpoint molecule often over expressed on tumor cells. PD-L1 interacts with its receptor PD-1 on T cells and suppresses their tumor killing activity. Recent clinical trials with PD-1 and PD-L1 inhibitors have demonstrated how blocking this immune checkpoint can unleash the power of our own immune system to fight cancer cells. Patients with cancers of notoriously poor prognoses, such as melanoma, have shown dramatic increases in clinical response and overall survival when treated with immune checkpoint inhibitors as part of their therapy. This breakthrough has led to clinical trials in patients with numerous cancer types. Dr. Gopal (Clinical Research Division) and Dr. Smith (UW Medical Oncology) sought to understand whether treatment with pembrolizumab, an antibody PD-1 inhibitor, would increase response rate in patients with diffuse large B cell lymphoma (DLBCL) when combined with current standard of care. Their results were recently published in the British Journal of Haematology.

DLBCL is currently treated with a cocktail of five chemotherapies (called R-CHOP) and is curable in many patients. However, the cancer is heterogeneous and standard of care does not work for all patients. Increasing intensity of R-CHOP treatment has not been effective in refractory patients. Of note, expression of PD-L1 on tumor cells has been associated with poor response to R-CHOP. This observation was the rationale behind testing whether adding PD-1/PD-L1 blockade to first line therapy would be safe and effective for DLBCL patients. 30 adults with previously untreated disease were treated in the trial. Patients were given pembrolizimab, a PD-1 inhibitor, the day before cycle 1 of R-CHOP and concurrently with cycles 2-6. Three patients did not complete the full 6 cycles – one due to early death in cycle 1, one due to disease progression, and one due to a serious adverse event (SAE) during treatment. In all, 17 SAE were noted during treatment in 13 patients, not uncommon during intensive chemotherapy. However, only 4 patients experienced potential immune-related adverse events, a potential side effect of PD-L1 blockade.

The overall response rate to pembrolizumab combined with R-CHOP was 90%, including 23 patients with a complete response – full clearance of their cancer. At 24 months post treatment, the overall survival was 84%. While this trial had a single-arm design and therefore could not be used to make direct comparisons to R-CHOP without pembrolizimub, Dr. Gopal said: “these data are the first to show that adding anti-PD-1 therapy to the initial standard treatment for the most common lymphoma is safe, feasible, and may overcome the expected adverse outcome of PD-L1 expressing disease.” In addition to collecting data on toxicity and response rate, the authors analyzed expression of PD-L1 on patient tumor samples. While PD-L1 expression was correlated with decreased response to R-CHOP in previous studies, when PD-1 blockade was added to treatment, high expression of PD-L1 was correlated with increased response to combination therapy, suggesting that PD-L1 expression is a key immune evasion strategy in DLBCL. Overcoming this evasion may allow patients with previously poor response rates to successfully fight their cancer. 

T cells surround and interact with a cancer cell. Once activated, the T cells will release cytotoxic granules to kill the cancer cells
T cells surround and interact with a cancer cell. Once activated, the T cells will release cytotoxic granules to kill the cancer cells WikiCommons

This work was supported by funding from Merck Sharpe and Dohme Corp, the National Institutes of Health, and donations from Frank and Betty Vandermeer and Sonya and Tom Campion.

Fred Hutch/UW Cancer Consortium members Stephan Smith, Brian Till, Mazyar Shadman, Ryan Lynch, Andrew Cowan, Qian Wu, Chaitra Ujjani, Andrei Shustov, Ryan Cassaday, Jonathan Fromm, and Ajay Gopal contributed to this work.

Stephen D. Smith, Brian G. Till, Mazyar S. Shadman, Ryan C. Lynch, Andrew J. Cowan, Qian W. Wu, Jenna Voutsinas, Heather A. Rasmussen, Katherine Blue, Chaitra S. Ujjani, Andrei Shustov, Ryan D. Cassaday, Jonathan R. Fromm, Ajay K. Gopal. 2020. Pembrolizumab with R‐CHOP in previously untreated diffuse large B‐cell lymphoma: potential for biomarker driven therapy. British Journal of Haematology

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