Solid tumors have been a tougher nut to crack for CAR T cells than B-cell cancers, for two main reasons.

Solid tumors have an inhibitors microenvironment that has made it difficult to get durable responses. And identifying antigens as specific as the B-cell markers CD19 and CD22 has been challenging, leading to problems with on-target, off-tumor toxicity.

At the 2022 Annual Meeting of the American Association for Cancer Research (AACR 2022), researchers reported heartening early clinical data in tough indications. Meanwhile, papers in the April 13, 2022, issues of Nature and Science Translational Medicine gave new research insights into how to make CAR T cells fit for solid tumors.

At the clinical trials plenary session, the reactions could have been taken from movie review blurbs. "I cried," session co-chair Marcela Maus told presenter Robbie Majzner during the discussion of his presentation.

Seeing Majzner's talk, it was easy to understand why.

The presentation was surely not a fairy-tale ending. Seven of 11 trial participants have died of their disease. But it reported significant inroads against what Majzner called "possibly the worst diagnosis in pediatric oncology."

That diagnosis is diffuse midline gliomas, which can occur in the brainstem or spinal cord of children and young adults. They are uniformly fatal, often within a year of diagnosis.

Majzner, who is an assistant professor of pediatrics at Stanford University, reported on a group of 11 patients who received GD2-targeted CAR T cells.

Nine of 11 patients had stable disease or an objective response, with 2 responses ongoing, and 5 responses lasting at least 6 months.

If patients responded to the initial, intravenous administration of CAR T cells, they could receive additional doses administered directly into the cerebral ventricles.

Also at the clinical trials plenary session, John Haanen, research group leader at the Netherlands Cancer Institute, presented data on BNT-211 (BioNtech Cell & Gene Therapies), which combines a claudin-6 targeting CAR T cell with a claudin-6 encoding mRNA vaccine (CARvac) designed to increase the persistence of the CAR Ts. Patients received one dose of CAR T cells, followed by repeated injections of CARvac.

The treatment led to a disease control rate of 86%, and an overall response rate of 43% in 14 evaluable patients, with 1 complete response, though responses were less durable than those reported by the Stanford team. Only 1 response has lasted longer than 18 weeks.

During the discussion, Haanen said that his team is working to identify vaccine dosing schedules that could increase CAR T-cell persistence.

The preclinical work in Science Translational Medicine presented another strategy for revving up CAR T cells through the presentation of extra antigen. In this case, the investigators took advantage of the fact that CAR T cells still have their normal T-cell receptor in addition to the chimeric antigen receptor they are named for.

The researchers first taught the T cells to recognize the antigens from an oncolytic virus, and then combined CAR T treatment with administration of that virus. This strategy prolonged survival in mouse models of pediatric and adult gliomas as well as melanomas.

Maus, who is director of the cellular immunotherapy program at Massachusetts General Hospital, discussed the data from her lab's Nature paper at a session on CAR T cells.

In their paper, she and her team showed "a differential role for IFN-gamma blockade in liquid versus solid tumors," she told the audience.

IFN-gamma that is secreted by T cells, including CAR T cells, upregulates antigen presentation pathways. But while knocking out IFN-gamma did not affect the ability of CAR T to kill CD19-targeted cells in leukemia or lymphoma, its blockade or knockout impaired the ability of a mesothelin-directed CAR T cell to lyse pancreatic tumors.

In their paper, the authors write that "our work demonstrates that liquid and solid tumors differ in their interactions with CAR T cells and suggests that enhancing binding interactions between T cells and tumor cells may yield improved responses in solid tumors."

Or as Maus put it in her symposium talk: "It takes a village... at the CAR T tumor synapse in solid tumors."