麻豆传媒

LOUISVILLE, Ky. -- A CD70-targeted CAR T-cell therapy for advanced kidney cancer continued to show durable activity in treatment-refractory patients, according to updated results from a prospective study.

Overall, a fourth of patients with CD70 total positive score (TPS) ≥50 had objective responses to ALLO-316, increasing to 40% of patients with fludarabine/cyclophosphamide (FC) lymphodepletion. Additionally, three of six patients treated with a higher dose of the engineered therapy responded to the treatment.

A single infusion of ALLO-316 was associated with manageable safety profile, particularly after implementing a new strategy to minimize immune effector cell hemophagocytic lymphohistiocytosis-like syndrome, reported Ritesh R. Kotecha, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York City, at the International Kidney Cancer Symposium.

"We're starting to see ongoing and deepening responses, particularly in patients with high CD70 expression, after a single infusion of ALLO-316," said Kotecha. "From a translational perspective, we have seen a decrease after ALLO-316 infusion of the alloreactive host CD70-positive T cells. We see a manageable safety profile compared to other highly active CAR T-cell constructs."

"The phase I trial supports further evaluation of ALLO-316 in CD70-positive RCC [renal cell carcinoma] and other CD70-positive malignancies. Enrollment is ongoing at the phase Ib regimen [of FC lymphodepletion and higher dose]," he noted.

The current results involved a total of 34 patients with relapsed/refractory clear cell (cc) RCC and added to those of an earlier report on 18 treated with the CAR T-cell therapy.

Questions and Kudos

During a discussion that followed the presentation, Kotecha fielded multiple queries from the audience, beginning with an unidentified speaker who questioned whether investigators should have treated the eight patients who were CD70 negative.

"With so much retrospective data in terms of CD70 status, we had to start somewhere," said Kotecha. "It all comes down to whether we think that the actual tissue we're testing has the actual CD70 status of the patient we're treating. Some of these tissues are hard to find, and you can imagine that CD70 status of a patient who had a nephrectomy 5 years ago, and now they're presenting for a third-line, fourth-line treatment, that might not be the same CD70. Looking back, finding true benchmarks is really important, and it might be almost construct dependent."

"I think this is a call to some of the other CD70 trials that are potentially going to happen, in terms of how do we understand what is the right cutoff for potential activity," he added.

Another unidentified speaker asked whether response to treatment differed according to site of metastasis. Investigators are looking at that issue, said Kotecha, "but I don't think we have a clear sense of CD70 in particular sites. I will say that there have been responses not only in the primary kidney tumor but also in metastatic sites."

Matthew Campbell, MD, of the MD Anderson Cancer Center (MDACC) in Houston, asked about staffing a CAR T-cell program in kidney cancer: Will treatment be under the purview of genitourinary (GU) oncology or stem-cell transplantation or some shared arrangement? "How are you going to staff up, given the high level of needs that are currently required to safely take care of these patients in the immediate post-CAR-T setting?"

MSKCC has a dedicated cellular therapeutics service, but specialists from different services, such as GU oncology, collaborate in patient care, said Kotecha. Beyond resource intensiveness, CAR T-cell therapy for solid tumors involves a "huge" educational requirement and a "different scope of feelings."

"There are toxicities that might happen quite later, after cytokine release syndrome [CRS]," he said. "We are seeing CRS now, on the GU side, with some of the more intensive immune therapies, and their management is completely different. We're seeing a wave of solid-tumor malignancies, not just kidney cancer, but this is just becoming sort of futuristic."

A CAR T-cell program for kidney cancer and other solid malignancies should have "an incredibly robust rheumatology team with lots of experience in CAR-T, who can help guide management," added Sumanta Pal, MD, of City of Hope in Duarte, California. "That's an absolute must...Without that helping hand along the way, it's very, very difficult to run these studies."

Detailed evaluation and mitigation of toxicity are essential, but "we cannot be discouraged," said Nizar Tannir, MD, also of MDACC.

"The future is here today, and I'm a very strong proponent of continuing this path for these patients who have no other options." said Tannir, noting his 45-year career in kidney cancer. "Many of the patients enrolled in TRAVERSE were my patients, who were in six prior lines of therapy. They had no other options. So, yes, we have toxicities, we even have fatalities, but that's how the field started in acute leukemias and aplastic anemia in the late '70s and '80s. And here we are. We cure acute leukemias. So kudos to the investigators."

Background, Results

The choice of CD70 as a target came from recognition that about 80% of ccRCCs highly express the surface antigen, which has restricted expression in normal tissues. The ALLO-316 construct is an off-the-shelf product derived from HLA-unmatched healthy donors. The construct is designed to kill CD70+ tumor cells and CT70+ host T cells that can promote allo-rejection (), said Kotecha.

The phase Ia-b TRAVERSE study consisted of dose-escalation and dose-expansion phases. Phase Ib was designed to establish a phase II recommended dose and determine an appropriate CD70 TPS cutoff for potential pivotal studies.

Investigators in the multicenter trial enrolled 39 patients (median age 60; 90% male; median time since original diagnosis 43 months), 34 of whom underwent lymphodepletion and received a single infusion of the CAR T-cell product. Side effects were consistent with the known toxicities of an active CAR T-cell product and lymphodepletion, said Kotecha.

Almost two-thirds of the patients developed CRS; 50-60% developed fatigue, neutropenia, anemia, and nausea; and >40% developed pyrexia and thrombocytopenia. The most common grade ≥3 adverse events were neutropenia (51%), anemia (33%), and thrombocytopenia (26%). One patient had grade ≥3 CRS.

Infections occurred in 62% of patients and neurotoxicity in 44%, including grade ≥3 severity in 31% and 8%, respectively.

Among 26 patients enrolled in phase Ia, responses occurred in seven (27%), all of whom had TPS ≥50 (n=21). The highest response rate (40%) occurred in the 15 patients who had TPS ≥50 and FC lymphodepletion (as opposed to FC plus an antibiotic). No responses occurred in eight patients with CD70-negative tumors.

Among eight patients enrolled in phase Ib, three responded to treatment, including three of six who had TPS ≥50.

In phase Ia, confirmed objective response rates were 19% in all 26 patients and 27% in 15 patients who had TPS ≥50 and FC lymphodepletion. In phase Ib, two of eight patients had confirmed responses, both in the six-patient subgroup with FC and TPS ≥50.

"High vector copy number levels observed in tumor samples demonstrated extensive infiltration of ALLO-316 cells," said Kotecha. "ALLO-316 targeting of patient CD70-positive T cells is supported by CAR T-cell expansion and persistence. CAR T-cell expansion and persistence were superior in responders to nonresponders."

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