Novel combination strategies to enhance brentuximab vedotin efficacy in relapsed/refractory Hodgkin Lymphoma
Beckman Research Institute of the City of Hope
Project Term: July 1, 2018 - June 30, 2023
New, non-chemotherapy treatments that use a patient’s own immune system have transformed the treatment of Hodgkin lymphoma (cHL). Typically used in patients with cHL that is resistant to standard treatment, these immune therapies can control the disease for months to years. However, in the long run, most patients will not be cured and will have immunotherapy-resistant cHL. My research evaluates strategies for reversing resistance to brentuximab vedotin (BV) immunotherapy for cHL by combining BV with other treatments in clinical trials.
Hodgkin lymphoma (HL) is a cancer of the lymph nodes that is characterized by the presence of Hodgkin-Reed-Sternberg (HRS) cells. Although many patients are cured with chemotherapy, ~30% fail initial therapy and need further treatment. Brentuximab vedotin (BV) is an antibody- with an attached toxin that binds to CD30 molecules expressed at the surface of HRS cells. After BV encounters and then binds to the HL cells, it is internalized, and the toxic payload is released into the cell, killing it. BV is FDA approved for HL patients who have either relapsed or are no longer sensitive to the drug (refractory), a disease subset known as R/R. Although BV is effective against HL, patients who achieve only partial responses eventually relapse. We showed that resistance to BV is associated with an increased expression of the multidrug resistance molecule called MDR1, which actively pumps the BV toxin MMAE out of the cancer cells. We also have preclinical evidence that combining BV with drugs that inhibit the MDR1 protein enhances toxicity to the cancer cells and overcomes resistance to BV. Our results led to the development of a phase I clinical trial testing the combination of BV plus MDR1 inhibitors in patients with R/R HL. HL resides in an inflammatory microenvironment. This is the area in which the tumor cells reside and is made up of a number of different cell types, including a variety of immune cells, including many T cells. This tumor microenvironment influences HL survival through mechanisms that suppress an active anti-tumor immune response. The actual tumor cells account for only 1-5% of the tumor tissue. Therefore, the tumor microenvironment represents an ideal target for the development of new strategies to modulate the immune response in HL. Ibrutinib is a drug approved for the treatment of several blood cancers through its inhibition of the BTK molecule. In addition, ibrutinib inhibits the ITK molecule. ITK plays a critical role in T cell signaling, and treatment of patients with ibrutinib improves T cell number and function. We hypothesize that inhibition of ITK using ibrutinib will improve the T-cell immune response in the HL tumor microenvironment and will thereby enhance the efficacy of BV. To test this hypothesis, we designed a phase II clinical trial testing the combination of BV plus ibrutinib in patients with R/R HL. These two clinical trials will likely lead to the development of new treatment strategies for patients with R/R HL. The goal is to improve survival, enhance quality of life, and perhaps achieve cures for patients with Hodgkin lymphoma.