New Orleans—Of the many emerging therapeutic options discussed at the 2013 annual meeting of the American Society of Hematology (ASH), perhaps none have generated more impressive clinical activity than chimeric antigen receptor (CAR)-expressing T-cell therapy. Numerous small studies testing the gene-engineered therapy in highly challenging patients were presented. Repeatedly, the results showed complete and relatively durable remissions in patients who had exhausted practically all other lines of therapy.
For the brief time this strategy has been in clinical testing, “we are seeing some fantastic outcomes,” said Marco Davila, MD, PhD, a leukemia specialist at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City. He presented data on a series of 16 patients with B-cell acute lymphoblastic leukemia (B-ALL) who received CAR T cells. Other data were presented on the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). The construction of the CAR T cells used in these studies differs, but the principle is the same.
A form of adoptive immunotherapy, CARs join the antigen-binding domain of an antibody with the signaling domain of a T-cell receptor. T cells with the engineered CAR are specifically targeted and cytotoxic to the tumor cells that express that antigen. For the CAR therapy developed at MSKCC to treat B-ALL, T cells were first isolated from the patients scheduled to receive this therapy and then genetically modified for targeting the CD19 surface protein. This involved fusing the signaling domains of the CD28 co-stimulatory receptor and the zeta chain of the CD3 complex with antigen-binding domains of an anti-CD19 antibody. The 19-28z CAR T cells created by this technique, which can be engineered in less than two weeks, are then returned to the patient.
“CD19 antigens are expressed on all normal and malignant B cells,” Dr. Davila said. “Expression of the 19-28z CAR by a T cell promotes binding of the CD19 antigen and triggers cytotoxicity, cytokine release and proliferation upon engagement of CD19.”
Other CAR T cells, including those used for B-ALL, are constructed differently. For example, the same signaling domain was fused with the antigen-binding domains from a different anti-CD19 antibody to create the FMC63-28Z CAR T cell tested against B-ALL at the National Cancer Institute (NCI). Yet another CAR targeting CD19, modified with the 41BB co-stimulatory protein instead of CD28, was used against B-ALL in studies performed at the University of Pennsylvania. Promising data on all three CARs were presented at the 2013 ASH annual meeting.
The data presented on B-ALL by Dr. Davila was generally representative. Part of an experience with more than 60 patients treated at MSKCC with CAR T cells, all 16 of the B-ALL patients in this series had been pretreated heavily. Most of them had detectable disease at the time of CAR infusion.
Of the patients, 88% achieved a complete remission, which is very high given the advanced stage of the disease. Furthermore, most of these were not only complete responses, but complete molecular remissions (CMR), an indicator of even greater disease control. Dr. Davila recounted two representative cases in which CMR was attained within two weeks of the infusion, even though the bone marrow blast percentage before therapy exceeded 60%. Two months after therapy, both patients recovered complete bone marrow function with no evidence of disease. Seven of the 16 patients in the series overall have undergone stem cell transplant.
The side effects of CAR T-cell therapy include fever, malaise, hypotension and hypoxia, which appear to be related to cytokine release. This explains the correlation between the intensity of these side effects and tumor burden at the time of treatment. Notably, the only relapses observed so far occurred in patients who received steroids to manage these adverse events. Subsequent use of tocilizumab (Actemra, Hoffman-La Roche), an interleukin-6 inhibitor, reduced these adverse events without exerting any apparent effect on outcomes.
The feasibility of CAR therapy in patients with advanced disease and multiple previous therapies, including hematopoietic stem cell transplant (HSCT), was underscored in a series of 10 patients with a broader range of advanced cancers treated at the NCI. Although only three of these patients achieved a substantial regression of malignancy, it was noted that T cells could be collected, engineered for CAR and reinfused even in patients with multiple previous transplants. One such woman has remained in remission for 12 months after the CAR T-cell infusion despite three previous transplants.
“These results show, for the first time, that small numbers of donor-derived allogeneic anti-CD19 CAR T cells can cause regression of highly treatment-resistant B-cell malignancies after allogeneic HSCT without causing graft-versus-host disease,” said James Kochenderfer, MD, an investigator in the Experimental Transplantation and Immunology Branch of the NCI. In a separate study, he also reported six complete remissions with anti-CD19 CAR therapy in a series of 15 patients with refractory large B-cell lymphomas. It was identified as the first report of benefit with CAR therapy in this group of patients.
All of the studies presented at ASH were Phase I, so CAR T-cell therapy remains highly experimental. Noting that responses have not been as great in indolent lymphomas, Dr. Davila speculated that some forms of leukemia, such as B-ALL, may be better suited to this approach than others. For patients with highly advanced, refractory B-ALL, Dr. Davila indicated that referral to a clinical trial with CAR T-cell therapy is likely to become increasingly attractive if benefits are sustained.
Drs. Davila and Kochenderfer reported no relevant conflicts of interest.