Immuno-Oncology Resource Center

Immuno-Oncology Resource Center

Issue: October 2021
Source:

Healio Interview

Disclosures: A clinical trial award funded by a research alliance between University of Pennsylvania and Novartis Pharmaceuticals and Children's Hospital of Philadelphia Frontier Program supported this study. Maude reports consultant/advisory board roles with Novartis and Wugen; research funding from Novartis; and paid travel, accommodations and expenses from Kite Pharma/Gilead Sciences, Novartis and Wugen.
September 08, 2021
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Researchers use ‘humanized’ CAR T cells to improve treatment durability for patients with ALL

Issue: October 2021
Source:

Healio Interview

Disclosures: A clinical trial award funded by a research alliance between University of Pennsylvania and Novartis Pharmaceuticals and Children's Hospital of Philadelphia Frontier Program supported this study. Maude reports consultant/advisory board roles with Novartis and Wugen; research funding from Novartis; and paid travel, accommodations and expenses from Kite Pharma/Gilead Sciences, Novartis and Wugen.
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The FDA approved the first chimeric antigen receptor therapy in 2017, authorizing tisagenlecleucel for treatment of children or young adults with relapsed or refractory B-cell acute lymphoblastic leukemia.

More than 90% of patients with advanced or difficult-to-treat disease initially respond to therapy with CD19-directed CAR T cells. Despite this overwhelming initial success, response durability has been a concern. Long-term follow-up studies show nearly half of patients eventually experience disease progression.

Findings from a phase 1 trial of humanized CAR-T.
Data derived from Myers RM, et al. J Clin Oncol. 2021;doi:10.1200/JCO.20.03458.

One approach to enhance the durability of CAR T-cell therapy involves the use of gene editing to “humanize” the murine-based portions of manufactured cells to avoid an immune response and improve their persistence.

Photo of Shanon Maude
Shannon L. Maude

Shannon L. Maude, MD, PhD — attending physician at Children’s Hospital of Philadelphia (CHOP) and assistant professor of pediatrics at Perelman School of Medicine at University of Pennsylvania — spoke with Healio about how humanized CAR T cells are developed, findings of a phase 1 trial conducted to evaluate this approach, and why it could prove effective for patients who relapse despite initial positive responses to CAR T-cell therapy.

Healio: What is a humanized CAR T cell?

Maude: Most CAR T cells originally were developed by taking a piece of mouse monoclonal antibody developed in mouse models and joining it to intracellular T-cell activation domains. Early on, researchers in the field — including our group — thought it was possible that the human immune system could recognize this piece of the CAR T cell as foreign and reject the cells, causing them not to last for a long period. We believe the long-term persistence of these T cells is part of what would make them effective and lead to durable remissions. Our team at Penn, in collaboration with Novartis, took the original design of tisagenlecleucel (Kymriah, Novartis) and changed some of the DNA sequences of the single-chain variable fragment domain — the antibody domain on the surface — so that when it encodes the protein that makes up the antibody, it looks more like a human protein. In this case, humanizing means we are altering this portion of the cells to look like a human protein, with the rationale being that this strategy could limit immune-mediated rejection of these T cells and lead to improved persistence.

Healio: What benefits do you anticipate from this approach?

Maude: The original trial was designed as a potential option for retreatment of patients after they experienced disease progression with a CD19-directed CAR-T. Patients who were treated with a murine-based CAR T-cell product and lost CAR T-cell persistence early after infusion were eligible for treatment on this trial to reestablish persistence of the CAR T cells. This approach could be effective as retreatment to reinduce remission for patients who had disease relapse and lead to a reestablishment of CAR-T cell persistence, and it could potentially increase the chances of prolonged persistence.

Healio: How did results from this study compare against your expectations?

Maude: I am encouraged by the results. The primary aim of the study was to assess safety and feasibility, but it ended up being a fairly large study, so we were able to get some efficacy signals, as well. The response rate in the retreatment cohort was 64%. This included patients who were both in remission and had reestablished B-cell aplasia, which we use as a marker of CAR T-cell persistence. There were durable remissions in the retreatment cohort, with a 1-year RFS rate of 74%.

After enrolling the first several retreatment patients, the trial was amended and allowed CAR-naive patients to be enrolled. The CAR-naive cohort had a 97% overall response rate, including a 100% response rate among patients with B-cell ALL. The 1-year RFS was 84% in that group, so these results gave us good information on initial efficacy and durability of responses.

We attempted to evaluate CAR T-cell persistence by comparing our investigational therapy with the murine-based commercial product tisagenlecleucel, which was developed by researchers at CHOP and the University of Pennsylvania. But the study numbers are small, so the trial was not powered to assess persistence.

However, we looked at early B-cell recovery, a sign of losing CD19-directed CAR T cells early after infusion. The proportion of patients who had early B-cell recovery after humanized CAR-T in this study was lower than it was with our initial phase 1 trial of tisagenlecleucel, but the difference was not statistically significant. Further study with a larger number of patients would be necessary to know if there truly is a difference in persistence.

Healio: Can you provide an update on the phase 2 portion of this study?

Maude: Similar to the phase 1 study, we are enrolling patients into retreatment and CAR-naive cohorts. The primary objective of the phase 2 study is EFS at 1 year after infusion. We want to assess the durability of responses in each of those two cohorts, but we will, of course, examine persistence and continue to monitor safety.

Healio: Have you encountered any surprises in this research?

Maude: We are learning that immune-mediated rejection or immunogenicity may play a role in poor CAR T-cell persistence for some patients, but it is likely not the answer to poor persistence for everyone. There have been patients in the retreatment cohort who have responded nicely to the humanized CD19 CAR-T but then lost their T cells early after infusion. This signals that, in some cases, lack of persistence may be more related to exhaustion of the T cells or other factors related to T-cell health. In the end, I don’t think we will find one answer that is generalizable for all patients.

Healio: What impact can humanized CAR-T have on clinical care of younger patients with advanced B-cell ALL?

Maude: It may have the largest impact for patients in the retreatment setting. Humanized CAR-T appears to be effective in this setting for patients, even those who had an initial response to conventional CD19 CAR T-cells but eventually experienced disease progression. The disease at that stage is very challenging to treat, so it was very encouraging — and I think clinically impactful — that we have a potential option for those patients and may be able to continue to improve on these therapies.

References:

Myers RM, et al. J Clin Oncol. 2021;doi:10.1200/JCO.20.03458.
Park JH, et al: N Engl J Med. 2018;doi:10.1056/NEJMoa1709919.

For more information:

Shannon L. Maude, MD, PhD, can be reached at The Children’s Hospital of Philadelphia, 3012 Colket Translational Research Building, 3501 Civic Center Blvd., Philadelphia, PA 19104; e-mail: maude@chop.edu.