Challenges, Opportunities for Improvement Persist in CAR T-Cell Treatment

April 2, 2021

Article

As more therapies continue to be approved, efforts will focus on toxicity prevention and mitigation strategies for associated unique and potentially life-threatening adverse reactions.

It’s been over 3 years since the cancer landscape entered a new frontier with the approval of 2 chimeric antigen receptor (CAR) T-cell therapies, including axicabtagene ciloleucel (Yescarta) for certain patients with B-cell non-Hodgkin lymphoma (B-NHL). The approvals brought immense medical innovation but also unique safety concerns.

Since the landmark approvals in 2017, addressing these safety concerns has been a priority, in addition to identifying other lymphomas CAR T-cell therapies could impact. Such research is the subject of a new review published in The Cancer Journal.

Research assessing CAR T-cell therapies in other lymphomas started to come to fruition with last year’s approval of brexucabtagene autoleucel (Tecartus) for the treatment of relapsed or refractory mantle cell lymphoma. Research is also testing whether CAR T-cell therapies can work in indolent B-NHLs, such as follicular lymphoma.

“Here, CAR T-cells may offer a potentially curative therapy for patients without other conventional curative options, thus revolutionizing treatment for B-NHL patients even further,” wrote the pair of researchers. “Despite these advances, CAR T-cell therapy remains plagued by several limitations including toxicity, resistance, and accessibility.”

As more of these therapies continue to be approved, efforts will continue to focus on toxicity prevention and mitigation strategies for the unique and potentially life-threatening adverse reactions associated with them, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

For example, in the ZUMA-1 trial of axicabtagene ciloleucel, CRS occurred in 93% of patients and was grade 3 or higher in 13%. There was a median of 2 days until onset of CRS, which lasted a median of 8 days.

“Understanding key mechanisms of both CRS and ICANS has identified potential targets for the use of prophylactic therapies,” authors said. “The recognition of the role that monocytes play in cytokine escalation, via secretion of interleukin (IL)-6 and IL-1, among other cytokines, has led to trials investigating drugs that neutralize granulocyte-macrophage colony-stimulating factor and IL-6 and that bind to and block the IL-1 receptor.”

Less toxic options will likely be a goal going forward in CAR T-cell therapy development. In February, the FDA granted approval to lisocabtagene maraleucel (Breyanzi), another option for certain patients with B-NHL but with less toxicity.

Resistance and relapse also pose challenges to these therapies, with 20% of patients with aggressive B-NHL expected to experience primary resistance and another 40% of responding patients eventually relapsing.

According to researchers, there have been multiple identified and proposed mechanisms of resistance, including loss of tumor antigen, which has been reported in up to 40% of aggressive N-NHL, immunosuppressive tumor microenvironment, and T-cell exhaustion.