This proposal addresses the Fiscal Year 2017 (FY17) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas of both Immunotherapy and Lymphoma. This proposal addresses the FY17 PRCRP Military Relevance Focus Areas of militarily relevant risk factors associated with cancer, particularly potential exposures to ionizing radiation and Agent Orange, which can lead to blood malignancies.

Non-Hodgkin lymphoma (NHL) presents a formidable challenge for developing effective anti-cancer therapies. While the cancer may initially respond to therapy, some tumors find ways to resist both the patient’s normal immune defenses and the chemotherapy/radiation treatments. Immunotherapy is a powerful new approach that directs and stimulates the patient’s immune system to combat cancer and is potentially more effective with less long-term toxicity than conventional chemotherapy and radiation treatments. In recent years, immunotherapy has shown long-lasting remissions in blood cancers, and in some solid cancers. We propose a cellular immunotherapy for NHL in which a patient’s own immune T cells are (1) removed from the blood, (2) genetically reprogrammed with chimeric antigen receptors (CARs) that can directly bind to the BAFF-R protein on malignant lymphoma cells, and (3) reintroduced into the patient’s bloodstream where they multiply, seek out and destroy tumor cells that display BAFF-R on the tumor cell surface. CAR T cell immunotherapy shows particularly impressive outcomes for B cell leukemias and lymphomas and is now under active investigation in solid cancers. Lymphoma represents a middle ground between blood and solid cancers: malignant cells form tumors in lymph nodes but can also travel through the blood and lymphatic system to metastasize.

Clinical results for CAR therapy targeting the tumor marker CD19 in lymphomas have demonstrated promising results. However, a serious issue in targeted immunotherapy is that tumor cells may escape from the anti-cancer treatment by mutating into a form that no longer displays the target on the tumor cell surface. In this case, CD19 is absent from the relapsed cancer cells -- a situation referred to as CD19-negative relapse. One idea to combat antigen escape is to develop a multi-pronged approach against several targets. The difficulty here is identifying suitable targets: the ideal target would be present on all tumor cells and absent on all healthy cells. We have identified a cell surface protein, BAFF-R (B-cell activating factor receptor), which plays a role in the normal development of B cells and is displayed on the surface of all B cells. It has been detected in large numbers on various B cell lymphomas, and as such, may be a good target for CAR T cell therapy. Our early experiments in mice testing a prototype BAFF-R CAR show promising results and are the basis of this proposal. We plan to further develop and optimize a BAFF-R CAR for clinical trials in humans. This new BAFF-R CAR has the potential to rescue patients who have relapsed after loss of the CD19 target. In the future if it is successful, the two CARs targeting different tumor proteins could be used together or in planned succession to combat cancer recurrence.

This proposed immunotherapeutic strategy is relevant to members of our military and their families, as it could provide additional effective means of treating combat-duty exposures to radiation or chemical exposures such as Agent Orange.