Slow Going With CAR T-Cell Therapy for Solid Tumors

Almost 4 years after the first chimeric antigen receptor (CAR) T-cell therapies received FDA approval, the transformative impact of the treatment on refractory hematologic malignancies has yet to translate into the field of solid tumors.

The increased molecular complexity of solid tumors and lack of good antigen targets have coalesced into a formidable roadblock for CAR T-cell development.

“Hematological cancers typically express a single, specific, tumor-associated antigen, whereas solid tumors have substantial antigen heterogeneity,” editors of Lancet Oncology wrote in an editorial. “Of concern, many antigens associated with solid tumors are also expressed on healthy tissue, raising the risk of off-target adverse events. Genetic modification technologies can help to circumvent this risk, but they are not a fail-safe solution.”

The editors cited several other major obstacles to CAR T-cell development for solid tumors:

1. Lack of appropriate cytokines in the tumor microenvironment to traffic CAR T cells to the tumor

2. How to maintain T-cell fitness over time

3. Lack of suitable chemotherapy regimens to facilitate lymphodepletion and CAR T-cell expansion

4. Overcoming immunosuppressive conditions in the tumor microenvironment

Small studies reported in 2019 at the American Society of Clinical Oncology and American Association for Cancer Research meetings showed early promise for CAR T-cell therapy in mesothelioma, sarcoma, and in gastric and pancreatic cancers. Additional preclinical and preliminary clinical studies reported in 2020 and this year have added to the understanding of how CAR T-cell therapy might carve out a role in solid tumors, but none of the studies yielded evidence of an impending transformative effect, as seen in hematologic malignancies.

CAR T-cell therapy for solid tumors encountered a setback in early June, when a trial of a promising strategy for prostate cancer was stopped because of two treatment-related deaths. Both patients died of immune effector cell-associated neurotoxicity syndrome (ICANS) following treatment with prostate-specific membrane antigen-directed CAR T cells that were also insensitive to transforming growth factor-beta, an immunosuppressive factor.

Early trials of the therapy had shown only one case (reversible) of cytokine release syndrome (CRS), according to the authors of the editorial. ICANS generally occurs less frequently than CRS but has been reported in as many as half of patients with hematologic malignancies treated with CAR T-cell therapy.

“Unlike CRS, the precise underlying pathophysiology of ICANS remains poorly understood, and although the acute symptoms of CRS and ICANS are generally reversible with supportive care, steroids, and immunosuppressive drugs, they can be associated with substantial morbidity, with some patients requiring admission to an intensive care unit,” the authors noted.

Investigation continues for another promising CAR T-cell strategy that might address two of the obstacles to development in solid tumors. Using a CAR T-cell technology known as synthetic Notch (synNotch), researchers at Children’s Hospital Los Angeles have developed engineered T cells that can precisely target specific types of cancer.

In ongoing studies for neuroblastoma, the synNotch protein on the surface of T cells recognizes the GD2 antigen, leading to CAR T-cell activation and recognition of a second antigen known as B7H3. The two-step, or gating, process helps minimize toxicity, as healthy cells sometimes express one of the antigens but rarely both of them, and neuroblastoma expresses both, the authors continued.

Increased stability of synNotch CAR T cells, as compared with regular constructs, addresses a second obstacle. Greater metabolic stability enables more prolonged tumor targeting, overcoming issues with CAR T-cell fitness.

“Despite many ongoing clinical trials, very few have reported any results, and all are at early stages. Consequently, many unknowns remain,” the editorial authors wrote. “The potential is evident, but it will only be realized through carefully designed trials incorporating thorough patient monitoring and stringent stopping rules, coupled to detailed preclinical translational research.”

A principal investigator for studies that led to approval of axicabtagene ciloleucel (Yescarta) said many studies of CAR T-cell therapy for solid tumors have been conducted, but little progress toward safe and effective constructs has occurred over the past several years.

“There are a whole lot of challenges, the biggest being the problem of identifying the right antigens that are targetable with CAR T cells in solid tumors,” Sattva Neelapu, MD, of the University of Texas MD Anderson Cancer Center in Houston, told MedPage Today. “I think that this editorial quite accurately points out that most of the antigens that are present in solid tumors may be present in normal tissues as well.”

“We need to invest more resources into identifying the right targets,” he added. “There may be some proteins that are post-translationally modified in a different way in tumor cells versus normal cells.”

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Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007. Follow

Disclosures

Authors of the editorial did not report any disclosures.

Neelapu has reported relationships with Squibb, Daiichi Sankyo, Celgene, Kite Pharma, and Novartis.

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