The target CD19 is the focus of many adoptive cell therapies, including chimeric antigen receptor T-cell (CAR-T) therapies. Although many understand the stunning efficacy seen in some patients with these therapies, less is known about what to do when the approach stops working as a result of the loss of CD19 on the surface of cancer cells. This mechanism, called antigen loss, may necessitate a second-generation approach to CAR-T design.
Researchers from various universities, including those from the Toni Stephenson Lymphoma Center in the Beckman Research Center at City of Hope, Duarte, California, think they have evidence of what could be a promising way to tackle antigen loss.
It’s through the use of BAFF-R-CAR T cells, or BAFF-R-CAR-T, and it demonstrated antitumor effects in lymphoma and acute lymphoblastic leukemia (ALL) lines and in a patient-derived xenograft. The humanized, second-generation CAR-T targets another marker specific to B cells, B-cell activating factor receptor (BAFF-R).
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In addition to being a National Cancer Institute-designated cancer center, City of Hope is part of “an elite group of institutions in the United States that have well-established platforms to manufacture clinical-grade CAR-T cells in its own cGMP facilities since the 1990s,” noted Hong Qin, MD, PhD, research professor in the department of hematology and hematopoietic cell transplantation at City of Hope.
Cancer Therapy Advisor sat down to speak to Dr Qin to find out more about the new CAR-T construct and how his research team thinks the new target could eventually help prevent the emergence of CD19 antigen loss.
Cancer Therapy Advisor (CTA): It seems as if BAFF-R-CAR-T therapies would be best used as a second line of defense after antigen escape. But, you saw that it actually performed better in animal models than CD19-directed CAR-T. If it wasn’t because of greater tumor antigen density, could you propose a reason for why you think you saw this result in mice?
Dr Qin: City of Hope continues to conduct more research on this experimental result, which was replicated both in vitro and in vivo. One potential reason could be that our BAFF-R antibody might have higher affinity and avidity to its target than [a] CD19 antibody.
CTA: Is BAFF-R expressed on normal, healthy cells, and if so, how would you manage the elimination of these healthy cells?
Dr Qin: BAFF-R is expressed on normal B cells and thus BAFF-R-CAR-T therapy can result in lymphopenia. However, we engineer our BAFF-R CAR with a safety switch, which is a truncated human EGFR. In severe cases, we can deplete BAFF-R CAR-T cells with cetuximab, a FDA-approved monoclonal antibody against EGFR, to correct lymphopenia.
CTA: Is there a potential for the eventual resistance to BAFF-R-CAR-T, just as we have seen with resistance to CD19-directed CAR-T?
Dr Qin: BAFF-R signaling is a driver of B-cell survival. This critical feature may limit the capacity of B-cell tumors to escape therapy by downregulation of BAFF-R expression. This scientific hypothesis will be tested in our first-in-human clinical trial.
CTA: Do you envision that BAFF-R-CAR-T could eventually be an option in multiple hematologic malignancies? If so, which ones?
Dr Qin: BAFF-R-CAR-T therapy can be used for multiple hematologic malignancies including non-Hodgkin lymphoma (follicular lymphoma, diffused large B-cell lymphoma, marginal zone lymphoma, mantle cell lymphoma, etc.), B-cell chronic lymphocytic leukemia and B-cell acute lymphoblastic leukemia.
CTA: Stimulatory domains in CAR-T: Is 4-1BB superior to other domains?
Dr Qin: We used a 4-1BB costimulatory domain for its critical role in T-cell survival.
CTA: Anything else you want to tell me about your work?
Dr Qin: City of Hope expects the first trial for BAFF-R-CAR T-cell therapy will open in about 6 months. We are excited about the prospect of providing a new treatment option — and hope — for patients who have relapsed after using CD19 CAR-T therapies.
Reference
Qin H, Dong Z, Wang X, et al. CAR T cells targeting BAFF-R can overcome CD19 antigen loss in B cell malignancies. Sci Transl Med. 2019;11(511):eaaw9414.
