ASCO: Advances in T cell therapies for lymphomas

Two studies led by MD Anderson researchers explore advancements in CAR T cell therapy for non-Hodgkin lymphomas. CAR T cell therapy is commonly used to treat large B-cell lymphoma and follicular lymphoma, which are types of non-Hodgkin lymphomas, and ongoing research focuses on minimizing toxicities and improving effectiveness, leading to better therapeutic outcomes for patients. Initial results from both studies were shared at the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting.

Allogeneic CAR T cell therapy shows promise in first-in-human clinical trial (abstract 8002)

Autologous CAR T cell therapy, in which CAR T cells are engineered from a patient’s own T cells, is effective against advanced non-Hodgkin lymphomas, but often, creating the therapy can be logistically challenging. Allogeneic CAR T cell therapy, in which CAR T cells are manufactured from a healthy donor, addresses these challenges. Data from the Phase I ALPHA clinical trial found that conditioning with ALLO-647, an anti-CD52 monoclonal antibody, followed by treatment with ALLO-501, an allogeneic anti-CD19 CAR T cell product, is safe and potentially effective against relapsed or refractory large B-cell lymphoma and follicular lymphoma.

The risk of graft-versus-host disease (GVHD) is reduced in ALLO-501 by genetically removing the T cell receptor. Further genetic modification allowed the use of ALLO-647 to selectively prolong lymphodepletion, which is the process of reducing the number of normal lymphocytes before infusing patients with CAR T cells. This selective conditioning with ALLO-647 delays rejection of ALLO-501 CAR T cells by the host and improves their persistence.

At the time of data collection, 12 patients were enrolled in the clinical trial at six centers in the U.S., and nine patients were treated with ALLO-501 at three dose levels. The overall response rate was 78%, with three complete and four partial responses.

The most common Grade 3 or 4 adverse events were neutropenia (55.6%), leukopenia (33.3%) and anemia (22.2%). Two of the treated patients developed grade 1 or 2 cytokine release syndrome, which resolved within 72 hours without the use of tocilizumab or corticosteroids. To date, there have been no GVHD or dose-limiting toxicities.

“Although early, these findings will indicate that allogeneic CAR T cell therapy can be safe and induce significant responses in patients with relapsed or refractory B-cell non-Hodgkin lymphomas. Longer follow-up is needed to determine durability of the responses,” says lead author Sattva Neelapu, M.D., professor of Lymphoma and Myeloma. “Based on these findings, enrollment is ongoing at higher doses of ALLO-647 conditioning and higher doses of ALLO-501.”

The clinical trial continues enrolling patients, and additional safety and efficacy data is being presented at the conference. See the abstract and co-authors here.

Early and prolonged use of corticosteroids can reduce the effectiveness of CAR T cell therapies (abstract 8011)

When severe side effects to CAR T cell therapy occur, corticosteroids are commonly prescribed to manage them. MD Anderson researchers examined whether corticosteroid therapy could affect the clinical efficacy of CAR T cell therapy, as well as whether the duration, dose or timing of corticosteroid treatment could impact clinical outcomes.

Their findings suggest that early and prolonged use of high-dose corticosteroids is associated with early disease progression and death in patients with large B-cell lymphoma (LBCL) who were treated with axi-cel, a type of CAR T cell therapy.

In a retrospective analysis of 100 patients with relapsed or refractory large B-cell lymphoma who were treated with standard of care axi-cel, researchers found that 60% of the patients had received corticosteroids to manage toxicities. The use of any dose of corticosteroids was associated with shorter progression-free survival (PFS), with those receiving corticosteroids having a median progression-free survival of six months versus nine months for those who did not receive steroids.

Further, the use of high-dose corticosteroids was significantly associated with shorter progression-free survival. Those receiving corticosteroids had a median progression-free survival of two months versus nine months for those who did not receive steroids. Prolonged use of corticosteroids, longer than 10 days, and earlier use of corticosteroids, in the first 7 days following axi-cel therapy, were also associated with shorter progression-free survival.

“Novel corticosteroid-sparing strategies are desperately needed for the treatment of toxicities associated with the use of CAR T cell therapy” says Paolo Strati, M.D., lead author of the study and assistant professor of Lymphoma and Myeloma. “Next, we hope to conduct additional evaluation to understand the mechanisms underlying the association between corticosteroid therapy and early disease progression. Additionally, we will soon open a clinical trial investigating the safety and efficacy of anakinra, an IL-1 receptor antagonist, to mitigate CAR T cell therapy-associated toxicities; pre-clinical and retrospective clinical data supporting its use are promising, and we are excited to see how the study will unfold.”

See the abstract and co-authors here.