Researchers Outline Potential Strategies for Overcoming CAR T Therapy Challenges

Jaime Rosenberg

Strategies for improving outcomes across hematologic cancers and solid tumors range from addressing cytokine release syndrome and neurotoxicity mediators, immune rejection, on-target off-tumor toxicity, post-infusion control limitation, and immunosuppressive tumor microenvironment.

As researchers continue to try and bring the promise of chimeric antigen receptor (CAR) T-cell therapy to solid tumors, a group of researchers is outlining emerging strategies for mitigating the barriers that to date have blocked successful outcomes in this setting.

The group also highlights that although CAR T-cell therapy has made strides in hematologic cancers like B-cell acute lymphoblastic leukemia, toxicities associated with the therapy and limitations of efficacy leave further room for improvement.

“In 2018, the American Society of Clinical Oncology (ASCO) named CAR T cell therapy ‘Advance of the Year’ which further highlights the key role of this fighting soldier in the cancer treatment revolution,” wrote the group. “However, CAR T cell therapy toxicities and limitations appear as stones thrown at its fragile success. Therefore, clinical and basic science research efforts are highly required for addressing these ongoing/unsolved caveats.”

Strategies for improving outcomes across hematologic cancers and solid tumors range from addressing cytokine release syndrome (CRS) and neurotoxicity mediators, immune rejection, on-target off-tumor toxicity, post-infusion control limitation, and immunosuppressive tumor microenvironment (TME).

According to the researchers, leveraging granulocyte-macrophage colony-stimulating factor (GM-CSF) blockade, catecholamine blockade, and IL-1 and IL-6 blockade have shown signs of promise for mitigating CRS, the most common side effect of CAR T-cell therapy. For example, in preclinical models, neutralizing GM-CSF with monoclonal antibodies such as lenzilumab showed a substantial reduction in myeloid and T cell infiltration in the central nervous system, preventing CAR T cell-mediated CRS.

Targeting the autoimmune defense receptor, CD47 expression, and T cell receptor and human leukocyte antigen knock outs have demonstrated potential for fighting immune rejection of CAR T-cell therapy. According to the researchers, one of the most recent approaches to addressing allogeneic CAR T-cell rejection involves the 4-1BB cell surface receptor protein on T and NK cells.

“So far, various attempts have been made for controlling the activity of CAR T cells after their infusion into patients,” wrote the researchers. “This topic deserves special attention since it can contribute to the control and prevention of the previously mentioned CAR T cell- mediated toxicities which can sometimes be life-threatening.”

Some research has suggested that inhibiting the lymphocyte-specific protein tyrosine kinase (LCK) can overcome the post-infusion control limitation. Tyrosine kinase inhibitor dasatinib inhibits LCK, thus preventing the phosphorylation of CD3z and ZAP70, and some researchers have leveraged the treatment to try and increase the safety index of CAR T cells.

In an attempt to overcome immunosuppressive TME, researchers have indicated the metabolic reprogramming of CAR T cells by modifying the expression levels of metabolic genes.

“This topic has been at the center of T cell reprogramming investigations since it has recently shown encouraging results. In this regard, it has been found that leukemic cells inhibit the Akt/mTORC1 signaling of T cells triggering their impaired functionality,” explained the researchers.

Reference

Kozani P, Kozani P, Rahbarizadeh F, Nikkhoi S. Strategies for dodging the obstacles in CAR T cell therapy. Front Oncol. Published online April 1, 2021. doi:10.3389/fonc.2021.627549