Myriad Strategies Being Developed to Fight Resistance in CAR T-Cell Therapy for Hematological Malignancies

One of the most promising advances in the treatment of hematologic malignancies in recent years has been the development of chimeric antigen receptor (CAR) T cells, which are reprogrammed T lymphocytes that can track and kill antigen-expressing cancer cells.

However, for all its potential, CAR T-cell therapy has one major flaw: a significant subset of patients with complete responses (CRs) to the treatment eventually relapse. For those patients, therapeutic resistance leads to a very poor prognosis.

In a review article in the journal Therapeutic Advances in Medical Oncology, corresponding author Mingzhi Zhang, MD, PhD, of the First Affiliated Hospital of Zhengzhou Universit, in China, and colleagues outlined some of the latest research in the effort to overcome this problem.

They began by reviewing existing CR data. In patients with B-cell acute lymphoblastic leukemia, CR rates range from 60% to 90%. However, 30% to 50% of these patients will go on to relapse, according to existing studies. The majority of those patients were CD19-negative, the investigators wrote.

In B-cell lymphoma, one study found a CR rate of 54%. Another study of patients with chronic lymphocytic leukemia reported a lower CR rate of 29%. However, relapse rates continue to be troubling in those malignancies as well.

The mechanisms of relapse can be broadly divided into 2 categories, Zhang and colleagues wrote. The first, antigen-positive relapses, appear to be linked with a lack of persistence of CAR T cells and are sometimes due to a suppressive tumor microenvironment. The other type, antigen-negative relapses, is not as well understood. However, studies have probed hypotheses such as epitope-masking, lineages switches, receptor gene mutations, and antigen downregulation, the investigators explained.

Efforts to fix the problem of relapse have been many. One strategy, Zhang and colleagues wrote, is to improve the design of CAR T cells, such as by finding better ways to select the most potent effector cells when creating them. There is also evidence that antigen density is tied to the effectiveness and durability of the CAR T cells.

Other efforts include attempts to replace the use of murine CAR single-chain variable fragment (scFv) with fully human CARs. Early evidence suggests these CARs might overcome limitations of existing cells.

“Specifically, fully human CD19-specific scFvs were more effective in lysing CD19-positive target cells, produced higher levels of cytokines, and proliferated more after activation compared with murine scFv,” Zhang and colleagues said.

Another strategy is the development of so-called “armored” CAR T cells. These cells are so named because they are modified to express both cytokines and costimulatory molecules by creating a pro-inflammatory tumor microenvironment.

Armored CAR T cells are not the only attempt to improve the durability of CAR T cells by changing the tumor microenvironment. Other investigators are looking at strategies such as chemotherapy and radiotherapy to remove regulatory T cells. CAR T-cell therapy could also be made more effective by combining it with other agents, such as Bruton tyrosine kinase inhibitors, the authors said.

Universal CAR T cells and multitarget CAR T cells are also being discussed and developed, they wrote.

In closing, Zhang and colleagues said there are a lot of possibilities being developed at the moment, but they said more questions than answers remain.

“However, the effectiveness of the aforementioned treatments remains unclear,” they said. “Thus, further research is needed to maximise the duration of responses while minimising the risk of relapse.”

Reference

Cai Q, Zhang M, Li Z. Potential strategies against resistance to CAR T-cell therapy in haematological malignancies. Ther Adv Med Oncol. Published online October 13, 2020. doi:10.1177/1758835920962963