Researcher Looks Ahead to Future Improvements in CAR T

Improvements in chimeric antigen receptor (CAR) T-cell therapy, approved last year by the FDA for leukemias and lymphomas, were a focus of a session by a National Cancer Institute (NCI) researcher who spoke at the CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference taking place in New York City this week.

Along with other researchers, James N. Kochenderfer’s previous work on CD-19 played a role in CAR T-cell therapy for lymphoma and leukemia and led to axicabtagene ciloleucel (Yescarta), for adult patients with relapsed or refractory large B-cell lymphoma, and sold by Kite. That therapy was approved by the FDA last year. The other one on the market is

tisagenlecleucel (Kymriah), approved for children and young adults with B-cell acute lymphoblastic leukemia (ALL), and is sold by Novartis.

Read more about CAR T research.

Kochenderfer spoke about how his current research builds upon his earlier work, which showed, among other things, that giving low-dose chemotherapy to a patient before a T-cell infusion led to fewer toxic affects.

He updated results from a study published last year regarding an initial study of a CAR that induced complete remissions (CRs) of diffuse large B cell lymphoma (DLBCL). The patients, who had relapsed disease, first received high-dose chemotherapy (cyclophosphamide and fludarabine) before the CAR was administered.

Five of the 7 patients obtained CRs, and 4 of the 5 patients had CRs that were long-term durations of remission.

Kochenderfer discussed 2 reasons why the patients had long-term responses, whether or not their CD18 cells were completely eradicated. One possibility is that perhaps the CAR T cells killed all lymphoma cells early after infusion, so long-term T-cell persistence is not really important.

Another possibility is that the CAR-T cells do not eliminate all lymphoma cells, and in this case, CAR-T cells persist to prevent relapse. This would mean CAR-T cell numbers, which are at their highest earliest in the infusion process, continue to prevent relapse years after infusion.

However, he said believes the first theory, based on the B cell count in the 4 patients, who had a recovery of normal B cells. It demonstrated that DLBCL remission can continue after the disappearance of functionally effective anti-CD19 CAR T-cell populations.

Overall, there was a response in 73% of patients and a CR was achieved in 55% of patients. A PR was achieved in 18% of patients. The biggest problem was the issue of neurologic toxicity, which affected 55% of patients.

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Current work is aimed at improving the CAR so that there are fewer toxic affects, he said. Researchers are doing this by using fully-human variable regions and by evaluating different hinge and transmembrane designs.

In a dose escalation trial, an improved CAR (FMC63-28Z) had similar efficacy, but fewer neurotoxic effects —just 1 patient out of 20 had neurotoxicity. Those results are still preliminary, he said.

He also discussed briefly discussed the NCI’s multiple myeloma work, which targets B-cell maturation antigen (BCMA), a member of the tumor necrosis factor superfamily. BCMA is expressed in normal human plasma cells. It is not expressed in any other tissues, he said. BCMA is expressed in almost all cases of multiple myeloma.

In a trial of 16 patients who received the highest dose of CAR-BCMA T cells, the overall response rate was 81%; 3% had a CR or a PR. The CAR-BCMA was the first tested in humans.