乌鸦传媒

A novel chimeric antigen receptor (CAR) T-cell therapy targeting CD70 showed encouraging activity in a small group of patients with advanced clear cell renal cell carcinoma (ccRCC), with one patient achieving a complete response (CR) lasting more than 2 years.

"To our knowledge, this durable CR is the first to be achieved with allogeneic CAR T-cell therapy in patients with relapsed and refractory solid tumors," said Sumanta Pal, MD, of the City of Hope Comprehensive Cancer Center in Duarte, California, who reported the results at the Society for Immunotherapy of Cancer (SITC) annual meeting in Boston.

Among 13 evaluable patients in the first-in-human trial, the allogeneic CRISPR/Cas9-engineered CAR T-cell product (CTX130) also led to stable disease in nine additional patients, resulting in a disease control rate of 77%, with the longest duration of stable disease ongoing at 7.8 months.

"During a period of stable disease -- and I think this is a really critical point -- patients did not receive any other anticancer therapies," said Pal. "This mitigated their exposure to other toxic agents -- VEGF inhibitors, TOR inhibitors, and so forth."

"This is quite clinically meaningful," he added.

As for safety, there were no dose-limiting toxicities across all dose levels of the therapy, Pal observed. While seven patients in the study experienced grade 1-2 cytokine release syndrome (CRS), there were no cases of grade ≥3 CRS. Three patients experienced serious adverse events (SAEs) related to CTX130, all of which were episodes of CRS. Three patients had SAEs of infections, all unrelated to CTX130, including a grade 5 pneumonia, with grade 4 dyspnea resulting in death.

No patients experienced immune effector cell-associated neurotoxicity syndrome, graft versus host disease, or hemophagocytic lymphohistiocytosis.

In an earlier SITC press briefing, Pamela Ohashi, PhD, of Princess Margaret Cancer Centre in Toronto, highlighted the fact that CTX130 is an allogeneic CAR T-cell therapy. "This means that this is thought to be an off-the-shelf product," she said. "When we think of transplants, usually we want syngeneic transplants; you want to have transplants matched. In a sense, this is a transplant unmatched therapy, so it is very exciting that this has really worked so well."

ccRCC is the most common histologic subtype of RCC and is often unresponsive to available therapies, including radiation, chemotherapy, and immunotherapy, Pal explained. "CD70 is a ligand for CD27 with transient expression on activated lymphocytes and is highly expressed in ccRCC tumor cells."

The phase I, open-label, multicenter, single-arm included 14 patients (median age 64.5) with unresectable or metastatic RCC with clear cell differentiation, who had progressed after prior exposure to checkpoint and VEGF inhibitors. All patients had either intermediate or high-risk disease, and median CD70 expression level on tumors was 100%.

Patients received CTX130 at dose levels ranging from 3x10⁷ to 9x10⁸ CAR T cells.

The patient who achieved the CR is a male, age 64, diagnosed with ccRCC in 2017. He received a prior line of therapy with cabozantinib (Cabometyx) and atezolizumab (Tecentriq).

"This particular patient really suffered quite extensively from chronic toxicities from those therapies -- hand-foot syndrome and diarrhea -- what you might expect from targeted therapy," Pal said. "He had multiple pleural lesions that evolved subsequent to therapy with cabozantinib and atezolizumab."

The patient was placed on CTX130. By day 42, after a single infusion of CGTX130, he achieved a partial response that evolved into a CR by month 3. That response has persisted past 24 months, "which is quite exciting," Pal said. "The patient only incurred grade 1 or 2 AEs, and had no AEs considered to be related to CTX130."

"CTX130 represents a proof-of-concept for further exploration of CD70-targeted CAR T-cells in ccRCC and other CD70-positive malignancies," Pal concluded, adding that the therapy is being developed with second-generation edits (as CTX131), containing disruption of Regnase-1 and TGFβR2, "which, when edited together, we think increases potency by at least 10-fold in preclinical models."

In September, CTX130's developer announced that the agent was granted an FDA Regenerative Medicine Advanced Therapy designation for the treatment of .

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