Ned Pagliarulo @NedPagliarulo
CAR-T cell therapy, which to date has proved most effective in treating blood cancers, could still have a future in treating some advanced-stage solid tumors like mesothelioma or sarcoma, results from two small studies presented Sunday at the American Association for Cancer Research's annual meeting suggest.
The research, conducted separately by investigators at Memorial Sloan Kettering (MSK) Cancer Center and Baylor College of Medicine, is notable because of the greater clinical challenges presented by solid tumors, which tend to be less susceptible to cancer cell therapy.
"Our trial shows early evidence that efficacy is possible," wrote Shoba Navai, an assistant progress of pediatrics at the Center for Cell and Gene Therapy at Baylor, Texas Children's Hospital and Houston Methodist Hospital and co-investigator of one of the studies, to BioPharma Dive.
Researchers and drugmakers alike are working to replicate cancer cell therapy's blood cancer successes in solid tumors, which account for many of the cancer diagnoses in the U.S. each year.
But several hurdles have slowed progress. Unlike leukemia and lymphoma, solid tumors are more heterogenous and express a wider array of tumor proteins — making it difficult to target CAR-T therapies to effectively seek out tumors.
"Not all cells within the tumor will express the same tumor proteins, so targeting only one protein may limit the efficacy of CAR T cells," wrote Baylor's Navai in an email to BioPharma Dive. "Additionally, large solid masses present physical impediments to the entry of T cells."
Solid tumors are also more likely to grow in an environment that works against T cells, further limiting efficacy.
Still, many groups, including the University of Pennsylvania, Seattle Children's Hospital and the Moffit Cancer Center as well as Baylor and MSK, are advancing early-stage research efforts — some of which have been licensed to biotechs.
In the MSK study presented Sunday, which was led by the center's deputy chief of thoracic surgery Prasad Adusumilli, 21 patients with malignant pleural disease were given CAR-T cells engineered to target a cell surface protein called mesothelin.
Nineteen of those patients had mesothelioma, an aggressive solid tumor linked to asbestos exposure with a particularly poor prognosis.
Combination platinum-based chemotherapy, a treatment option approved for mesothelioma in 2003, results in a median overall survival of about 3 months, while early tests of checkpoint inhibitors like Merck & Co.'s Keytruda (pembrolizumab) have shown only modest response rates.
Data presented by Adusumilli on Sunday suggest mesothelin-targeted CAR-T therapy, combined with PD-1 inhibition, could be a path toward more effective treatment.
Of the 11 patients who received preconditioning chemotherapy followed by CAR-T and at least three cycles of anti-PD1 treatment, eight saw their tumors shrink. Two patients had complete metabolic responses to treatment, which remained ongoing at 60 weeks and 32 weeks.
Importantly, no evidence of CAR-T cell-related toxicity greater than Grade 2 was observed, and no patients experienced neurotoxicity or cytokine release syndrome — common side effects of CAR-T cell therapy.
"Yes, it's a Phase 1 study," said Adusumilli in an interview, "but it is exciting because it's not something we've seen in mesothelioma. It gives us optimism."
The combination treatment didn't benefit everyone, however; 12 of the full group of 21 patients eventually saw their cancers progress. Follow-up also remains early, and using a PD-1 inhibitor after CAR-T therapy makes for lengthy and intensive treatment.
Memorial Sloan Kettering has licensed its mesothelin-directed CAR-Ts to Atara Biotherapeutics, a South San Francisco, California-based biotech.
The Baylor study, which was led by the center's Meenakshi Hegde, tested a CAR-T targeted to HER2, a protein found across many different solid tumor types, most notably in breast cancer.
In this Phase 1 trial, which enrolled 10 patients with refractory or metastatic HER2 positive sarcomas, three complete responses were reported. One patient with rhabdomyosarcoma that had metastasized to the bone marrow went into a complete response for 12 months before relapsing. But reinfusion of the HER2 CAR-T therapy triggered another full response that remained ongoing at 17 months.
No patients in the study developed neurotoxicity, and only two experienced cytokine release syndrome greater than Grade 2.
Trial participants, however, received up to three infusions of CAR-T cells, and those who responded has as many as five more.
The reason for the intensive treatment, Navai explained, has to do with the persistence of CAR-T cells in the blood, which this and previous studies of HER2 CAR-T cells showed to be much more limited than what's been seen with CAR-T therapies for leukemia and lymphoma.
Such an approach also serves to highlight how much more difficult treating solid tumors can be, particularly when part of CAR-T's promise has been its potential as a one-time treatment.
Several drugmakers, including GlaxoSmithKline, TCR2 Therapeutics and Ziopharm, have turned to CAR-T's cousin — T cell receptor therapy — in hopes of solving the challenge of solid tumors.
Unlike CAR-T, TCRs tap into a natural signaling pathway and are capable of recognizing intracellular targets, rather than just those on the surface of a cancer cell.
There, too, however, work remains in early- to middle-stages, making cell therapy in solid tumors a field that's only just emerging.
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Filed Under: Clinical Trials