Going after CD70 with CAR T, NK Cells

Solid cancers pose a barrier that chimeric antigen receptor (CAR) therapies, whether engineered with T or natural killer (NK) cells, have yet to successfully hurdle. There may be some light at the end of the tunnel, however, with the emergence of CD70 as a feasible CAR target in renal cell carcinoma (RCC) and other tumor types.

CD70 is highly expressed in clear-cell RCC, the most common subtype of this disease, noted Sumanta Pal, MD, of City of Hope Comprehensive Cancer Center in Duarte, CA. By interacting with CD27, its natural ligand on T cells, CD70 is thought to contribute to the latter's exhaustion, besides expanding immunosuppressive regulatory T cells in the tumor microenvironment. At least one CD70-targeting monoclonal antibody, cusatuzumab (Argenx), is in development, but Pal and fellow investigators opted to assess the CAR approach instead with CTX130 (CRISPR Therapeutics).

“This is a first-in-class allogeneic CAR [T-cell therapy] against CD70,” Pal explained: CRISPR–Cas9 technology is harnessed to place the CAR construct in the TRAC locus of healthy donor T cells, which disables the native T-cell receptor, ensuring that the final product won't cause graft-versus-host disease.

Preliminary findings from Pal's phase I COBALT-RCC trial were presented during the Society for Immunotherapy of Cancer (SITC) Annual Meeting in Boston, MA, November 10–12. To date, 14 patients have received CTX130 at one of four different doses, from 30 million to 900 million cells. All were enrolled with inoperable metastatic disease that progressed despite immune checkpoint and VEGF inhibition. The main side effect was low-grade cytokine release syndrome. No neurotoxicity occurred, and overall, CTX130 “has an acceptable safety profile, with no unexpected on-target, off-tumor adverse events,” he said.

Among 13 patients evaluable for efficacy, the disease control rate was 77%. Nine patients experienced stable disease and one achieved a complete response “that's ongoing at 24 months, which is quite exciting. To our knowledge, it's the first such durable response with allogeneic CAR [T-cell therapy] in a relapsed/refractory solid tumor,” Pal said.

At The University of Texas MD Anderson Cancer Center in Houston, Katy Rezvani, MD, PhD, is also pursuing CD70 as “a promising pan-cancer antigen,” albeit using cord blood–derived NK cells. Her group previously established that these donor-generic cells, outfitted with a CD19 CAR, are a promising alternative to autologous CAR T-cell therapy in patients with non–Hodgkin lymphoma and chronic lymphocytic leukemia.

Rezvani's lab has developed CD70-targeting CAR NK cells and established their preclinical utility, she told SITC attendees; a phase I/II study is underway with the first patient enrolled. The therapy will be assessed in hematologic malignancies, RCC, osteosarcoma, and mesothelioma. This trial will also be the team's first to feature freeze-thawed—not freshly manufactured—CAR NK cells.

“We've known that cryopreservation is necessary for a truly off-the-shelf product,” Rezvani remarked, “but NK cells have been notoriously difficult to freeze,” unlike T cells. “After testing more than 90 methods over the last 3 years, I'm pleased to say we've finally found one” that maintains the cells’ viability and in vivo proliferative capacity.

Meanwhile, CTX130 “is currently undergoing second-generation edits,” Pal said. CRISPR–Cas9 will be deployed to disrupt both Regnase-1 and TGFβR in the new iteration, CTX131. Preclinical modeling has indicated that this move should increase therapeutic potency by at least tenfold.

COBALT-RCC “provides a proof of concept for further exploring CAR-based therapies” in CD70-positive cancers, Pal added. “We also have fairly robust translational data from our study that we're preparing to publish,” which should shed light on the engineered cells’ persistence, tumor trafficking, and other dynamics key to fine-tuning CTX131 for clinical evaluation in 2023. –Alissa Poh

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