Tumor shrinkage in brain cancer patients renews optimism for CAR-T in solid malignancies

By Jason Gale

A breakthrough therapy that can cure blood cancer generated a dramatic response in brain cancer, rekindling optimism that the technique using a patient’s own immune system might help fight solid tumors.

Tumors rapidly shrank within days in the first three glioblastoma patients who received the novel immunotherapy at Massachusetts General Hospital last spring. Although they eventually resumed growing, one patient’s cancer didn’t worsen for more than six months.

Glioblastoma, the most common brain malignancy in adults, is notoriously lethal, even with the best care. Most of the 14,000 Americans diagnosed each year die within 16 months. Preliminary results published in the New England Journal of Medicine on Wednesday offer a novel avenue for researchers trying to prolong the response in other patients.

“It’s still early, but we are very excited,” said Bryan Choi, a neurosurgeon and associate director of Mass General’s Center for Brain Tumor Immunology and Immunotherapy. “We hope that we can generate optimism in a field where the prognosis is so dismal.”

Past attempts at harnessing the immune system to fight glioblastoma have failed, leaving patients dependent on traditional drugs, radiation and chemotherapy that have been used for about 20 years with minimal improvement in average survival.

The complex therapy involves removing the patient’s T cells - the white blood cells in the immune system that protect against infection — and genetically modifying them to recognize and target tumor cells. They are then infused back into the patient.

Breakthrough Treatment

The resulting product, known as CAR-T therapy, has revolutionized the treatment of certain types of lymphoma, leukemia and myeloma. Efficacy against glioblastoma and most solid tumors remains elusive.

Marcela Maus, director of the cellular immunotherapy program at Mass General Cancer Center, spent years working on a new kind of CAR-T therapy that both targets common brain cancer cells and recruits T cell engaging antibody molecules, or TEAMS, that enhance tumor-killing.

The treatment is injected directly into the fluid that surrounds the brain via an Ommaya reservoir. The device, which sits under the scalp, provides access to patients’ cerebrospinal fluid. Samples of the liquid can be tested for cancer biomarkers, potentially providing another avenue for measuring tumor progression, Maus said.

The first patient treated experienced a rapid regression of his tumor in just one day. A single infusion shrank the second patient’s tumor 18.5% in two days, and it had decreased by 60.7 per cent on day 69, MRI scans showed. The third patient showed near-complete tumor regression on a scan done after five days. All three were being treated for tumors that had recurred after receiving standard care.

“We’ve been surprised at how dramatic these tumor responses are,” Maus said in an interview. She plans to test whether the effect can be prolonged by giving a small dose of chemotherapy prior to the infusion.

As many as 21 patients will be enrolled in the study, which is funded by Gateway for Cancer Research. It aims to gauge the safety, toxicity, and biological activity of the treatment.

All three participants had fevers that peaked within 48 hours of infusion and were treated intermittently with the anti-inflammatory drug anakinra, according to the study.

Next-Generation CAR-T

Early results using “next-generation” CAR-T cells indicate the TEAMS approach might help overcome some of the barriers hampering the treatment’s effectiveness in solid tumors, Choi said.

Six glioblastoma patients treated with another experimental CAR-T therapy showed an “encouraging early efficacy signal” in a study published Wednesday in Nature Medicine.

The research findings may reinvigorate the pharmaceutical industry’s interest in developing brain cancer therapies, Maus said.

“There’s been such a long history of failures that they see it as a very high-risk endeavor,” she said. “The most that I can hope for is that, even if we can only move the needle in a couple of patients, that somebody will see that it’s promising enough that they could move the needle for larger patient populations.”