Genetically engineered T cells effective for B-cell malignancies post allogeneic HSCT

ORLANDO, Fla. — The infusion of allogeneic anti-CD19 chimeric antigen receptor T cells following allogeneic hematopoietic stem cell transplantation induced remissions without causing graft-versus-host disease among patients with B-cell malignancies, according to research presented at the ASH Annual Meeting and Exposition.

Perspective from Marco L. Davila, MD, PhD

“Progressive malignancy is the leading cause of death among patients who underwent allogeneic hematopoietic stem cell transplantation [HSCT],” James N. Kochenderfer, MD, investigator in the experimental transplantation and immunology branch at the NCI’s Center for Cancer Research, told HemOnc Today. “One of the main treatments for progressive malignancy after allogeneic transplantation is infusion of unmanipulated allogeneic donor lymphocytes, which are very inconsistently effective and often cause graft-versus-host disease [GVHD].”

James N. Kochenderfer

Thus, Kochenderfer and colleagues investigated the efficacy of genetically engineered allogeneic T cells targeting the B-cell antigen CD19 as a treatment option in this population. Twenty patients with B-cell malignancies who underwent allogeneic HSCT received a single infusion of chimeric antigen receptor (CAR) T cells — derived from their HSCT donor — without chemotherapy or other therapeutic regimens.

Nine patients achieved remission (complete remission, n = 6; partial remission, n =2).

Patients with acute lymphoblastic leukemia (n = 5) achieved the highest response rate, with all but one patient obtaining minimal residual disease-negative complete remission. Responses also occurred in patients with chronic lymphocytic leukemia and lymphoma.

The longest ongoing complete remission (36 months) occurred in a patient with CLL.

Adverse events included fever, tachycardia and hypotension; however, no patient developed new-onset acute GVHD after T-cell infusion.

Patients who achieved remissions had a higher median peak blood CAR T-cell level than those who did not (median, 39 CAR-positive cell/mL vs. 2 CAR-positive cell/mL; P = .001).

Researchers noted the presence of endogenous normal or malignant blood B lymphocytes before infusion corresponded with higher post-infusion median blood CAR T cell levels (P = .004).

When compared with patients who did not achieve remission, patients in remission had a higher CD8–CD4 ratio of blood CAR-positive T cells at the time of peak CAR T-cell levels (P = .007).

The mean percentage of CAR-positive and CD8-positive T cells expressing PD-1 increased from 12% at time of infusion to 82% at time of peak blood CAR T-cell level (P < .0001), and the mean percentage of CAR-positive and CD4-positive T cells expressing PD-1 increased from 32% at time of infusion to 91% at time of peak blood CAR T-cell levels (P < .0001).

“Without chemotherapy or other treatments, allogeneic anti-CD19 T cells can cause remission of malignancies that were progressive, despite allogeneic transplantation, chemotherapy or other treatments,” Kochenderfer said. “The CAR cells did not cause GVHD. We are going to try to improve how the CAR T cells are manufactured in an attempt to improve efficacy.” – by Cameron Kelsall

Reference:

Brudno JN, et al. Abstract 99. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.

For more information:

James N. Kochenderfer, MD, can be reached at the NCI’s Center for Cancer Research, Building 10 – CRC – Room 3-3888, Bethesda, MD 20892; email: kochendj@mail.nih.edu.

Disclosure: Kochenderfer reports no relevant financial disclosures. Other study researchers report research funding from and consultant and speakers bureau roles with Allos, Biogen Idec, Celgene, Genentech, Gilead, Kite Pharma and Millennium Pharmaceuticals.

Perspective

Marco L. Davila, MD, PhD

This study included a series of 20 patients treated in a post-allogeneic hematopoietic stem cell transplantation setting who had experienced some recurrence of disease after transplant. Kochenderfer and colleagues have shown that you can actually infuse allogeneic CAR T cells in patients and have it be relatively safe. There has always been a concern that allogeneic CAR T cells has the potential to mediate GVHD, which is always the biggest concern in this patient population. But in this series of patients, there was no evidence of it.

In terms of outcomes, acute lymphoblastic leukemia remains the most susceptible disease to CD19-targeted allogeneic CAR T-cell therapy. Four out of five patients with ALL were induced into a complete remission; no other disease had that level of efficacy. Usually, you see one out of five. Again, we are stuck with the same broad differential in terms of efficacy with B-cell malignancies.

That being said, as the researchers emphasized, these patients were treated with CAR T cells without conditioning chemotherapy. This makes the outcomes very surprising. Many in the adoptive cell therapy field emphasize the dogma that you have to provide some kind of chemotherapy before T-cell infusion, so the fact that they were able to get any kind of outcomes was unexpected. Of course, there are some who suggested that the efficacy may be improved even more by giving some form of chemotherapy. But in general, it was a surprising outcome and shows that out of the data that have occurred in the last 5 years, autologous CD19 CAR Tcells have a lot of efficacy. It also is clear that in the post-transplant setting, there is a potential therapeutic window for allogeneic CAR T cells.

Marco L. Davila, MD, PhD

Moffitt Cancer Center

Disclosures: Davila reports a scientific advisory board position with Adaptive Biotechnologies.