Researchers Tackle Limitations, Opportunities of CAR T Cells in Solid Tumors

At the 2022 International Cancer Immunotherapy Conference in New York City, keynote speaker Crystal L. Mackall, MD, reviewed several studies with new findings about how future chimeric antigen receptor (CAR) T-cell therapy research could minimize the limitations of these treatments.

Mackall said it has been an exciting time in immuno-oncology research, particularly around CAR T-cell therapies. As of July 31, 2022, Mackall said there are 12 approvals, 6 products, and 2 targets in the CAR T space.

“I think, even for someone like myself, who was wowed by the first patient treated…with current T-cell therapies, I didn’t expect that their momentum and impact 10 years later would be as great as they [are],” Mackall said.

However, she added that one of the key limitations of CAR T-cell therapies thus far is their limited use in solid tumors. Until recently, Mackall said she believed that this use was limited at best, but new research has shown signals of activity. Mackall then highlighted several key studies examining the use of CAR T-cell therapies in solid tumors and some approaches to maximize their potential.

Firstly, Mackall said CAR T-cell therapy has shown significant potential benefit in diffuse midline glioma, which is a devastating pediatric tumor affecting school-age children and young adults. In addition to its devastating impacts, Mackall said there are no standard treatments for this tumor, and nearly all patients die.

Mackall said that researchers in her lab administered 1 infusion of GD2 CAR T cells in animal models to induce sustained eradication of diffuse midline glioma tumors and found promising results, although several animals died from toxicity-related issues. The team began planning to take this research into the clinic environment but knew that the GD2 CAR T-cells did not have the same potency as CD19-targeted CAR T-cells. As 2 researchers began tackling this issue, Mackall said another researcher investigated optimal administration routes for the therapy.

Notably, the team found that intracerebroventricular (ICV) delivery of CAR T was significantly more potent and less toxic than systemic delivery for the treatment of brain tumors. Mackall said that there was approximately 10-fold more potency, in addition to rapid internalization into the brain and lowered systemic cytokine levels.

Putting all of this together, the team has undertaken a phase 1, single-institution trial with 2 arms. Mackall reviewed findings from Arm A, which has found impressive, reproducible activity with the GD2 CAR cells.

In a patient example, the participant had an initial response followed by a recurrence, and then a response to retreatment following ICV infusion. Other participants include an 18-year-old who regained the ability to walk and is off to college, and a 4-year-old participant whose vision has significantly improved and who can now run and play on the playground.

“I think these are clearly promising early results, and this is really bringing together a variety of features that are a perfect storm that could allow this to happen,” Mackall said.

In a second research example, Mackall discussed the work of Zina Good, PhD, who is investigating biomarkers of clinical outcomes following axicabtagene ciloleucel therapy for large B-cell lymphoma (LBCL). Using machine learning, Good identified metaclusters associated with disease control and neurotoxicity. Metacluster 4 (CD4+Helios+CD25+) had a higher risk of disease progression and a lower risk of high-grade neurotoxicity. However, metaclusters 3 and 6 (CD4+CD57+ and CD8+CD57+, respectively) had a lower risk of disease progression.

Furthermore, Mackall said the team observed significantly elevated regulatory T-cell (Treg) levels in the cerebrospinal fluid of patients receiving intravenous GD2-CAR T cells, compared with those receiving ICV-infused cells.

Metacluster 4 also showed hallmark features of Tregs and showed broad T-cell receptor diversity. Therefore, Mackall said that stratification of patients based on pre-treatment lactate dehydrogenase and D7 CAR Treg levels could provide a powerful predictor of the risk for disease progression following treatment with axicabtagene ciloleucel.

Finally, Mackall reviewed the research of Dorota Klycz, PhD, who has been working on the issue of CD39+/CD8+ exhausted T-cells. Whereas knockout of CD39, CD73, and A2aR did not significantly enhance T cell potency, the team saw broad reprogramming with adenosine deaminase overexpression and even more potency with inosine exposure. Using inosine was found to induce stemness features and diminish terminal differentiation, in addition to modulating several metabolic enzymes and enhancing antitumor potency.

"[Research] has been primarily focused on B-cell or plasma-cell malignancies,” Mackall explained in her presentation. “From a principle standpoint, I think there’s no reason CAR T-cells can’t also work in solid tumors.”

Reference

Mackall, CL. Keynote. 2022 Cancer Immunotherapy Conference. September 28, 2022.