While chimeric antigen receptor T-cell (CAR-T) therapy has been making waves for the last few years as a novel treatment approach in cancer, the successes have remained mostly in the realm of blood cancers. This makes a first-in-human CAR-T clinical trial that targets a solid tumor growth receptor called MUC1* stand out. At the 34th Annual Meeting & Preconference Programs of the Society for Immunotherapy of Cancer, or SITC 2019, in November 2019, Minverva Biotechnologies shared an abstract offering some details behind this trial, which began in September 2019.1
Many clinical trials have tried to target the full-length MUC1 protein and have failed. The failures are likely due to the fact that MUC1 is cleaved and released from the tumor surface, meaning any therapy that binds with it goes too. When MUC1 is cleaved, however, the binding site for a crucial growth factor receptor that Minerva is calling MUC1* is revealed, said Cynthia Bamdad, PhD, CEO of Minerva.
Leaving MUC1* exposed and unattended is like “the pin being pulled on the hand grenade,” Dr Bamdad said. When a growth factor comes along and binds to the MUC1* receptor, it causes the cancer cells to grow and become resistant to chemotherapy.
Minerva’s new investigational CAR-T therapy aims to swoop in and bind to the MUC1* receptor to block growth factors from accessing the MUC1 cleavage product. This binding and blocking action can, theoretically, stop a tumor from growing. The CAR-T therapy also aims to kill any mutant cancer cells in its vicinity and send out a call to the patient’s immune system to produce more like-minded CAR-T cells to shrink the tumor.
“It’s a very unique approach to MUC1, and that’s why we emphasize that it’s different,” said Matt Britz, head of business development at Minerva, referring to a line in the company’s abstract that calls out previous failed trials that looked only at full-length MUC1 and not the MUC1* receptor.
Up to now, CAR-T therapy has been so specifically successful with blood cancers because they’re malignancies of B cells, which CAR T-cells can completely wipe out (it also can eliminate healthy B cells in the process, which can affect a patient’s ability to ward off infections). “The patient may get a sniffle more often, but is otherwise okay,” Dr Bamdad remarked.
But this same approach doesn’t work with solid tumors because they have no B-cell equivalent. It’s been a challenge to find a solid tumor target that is not also present on healthy cells, which, if wiped out, could negatively impact a patient’s chances of survival.
“Our approach is unique in that the CAR-T that we developed binds to the part of MUC1* that is masked on healthy tissue,” she said. “The CAR-T cells very selectively bind to and kill the tumor cells.”
Dr Bamdad also said that MUC1*, which is expressed aberrantly in 95% of breast cancers, 83% of ovarian cancers, 78% of pancreatic cancers, and 71% of lung cancers, is the closest thing there is to a B-cell equivalent in solid tumors.
“If this trial is successful, it will be a major step forward toward CAR-T cures for solid-tumor cancers, which make up 93% of all cancers,” Dr Bamdad added.
Britz said that an obstacle in getting CAR-T therapy to go mainstream is that it’s still seen as being prohibitively expensive — but he remains hopeful that as there are more successes in trials, there will be a parallel effort to bring the cost down. “I think we’re in a paradigm shift in the way that cancer is going to be treated,” he said.
Bamdad C, Stewart A, Huang P, Smagghe B, Moe S, Swanson T, Jeon T, Page D, Mathavan K, Grant T, Herrup R. Poster presented at: the 34th Annual Meeting & Preconference Programs (SITC 2019); November 6–10, 2019; National Harbor, MD. Abstract P150.