麻豆传媒

ORLANDO -- An off-the-shelf, allogeneic chimeric antigen receptor (CAR) T-cell therapy targeting CD70 demonstrated antitumor activity in patients with advanced clear cell renal cell carcinoma (RCC), according to results from the phase I .

Three of 18 efficacy-evaluable patients (17%) responded to treatment with ALLO-316, and the disease control rate (DCR) reached 89%, reported Samer Srour, MD, of the University of Texas MD Anderson Cancer Center in Houston.

All three responses involved patients with CD70-positive disease, leading to an objective response rate (ORR) of 30% in this subset of 10 patients. The DCR was 100% and the median progression-free survival was 5 months in this subgroup, Srour said during the American Association for Cancer Research (AACR) annual meeting.

Srour said he and his colleagues were "very encouraged" by the antitumor activity demonstrated in these patients who expressed CD70, particularly since they were treated at the lowest dose levels of 40 to 80×10⁶.

"With this off-the-shelf CAR T product, we are seeing encouraging antitumor activity with no unexpected safety signal," he added, noting that the median time from study enrollment to treatment initiation was 5 days, and as little as 1 day.

"This is very important when compared to autologous products, where it takes a minimum of 2.5 to 3 weeks," he said, suggesting that ALLO-316 meets an unmet need for patients who need urgent treatment.

AACR discussant John Haanen, MD, PhD, of the Netherlands Cancer Institute in Amsterdam, called CD70 "an interesting target for this disease." However, he added, "the target needs to be expressed, otherwise I don't think we should expose patients to this drug."

In explaining the rationale behind targeting CD70, Srour noted that while CAR T-cell therapy has been practice-changing in hematologic malignancies, "when it comes to solid tumors, we have been behind with CAR T-cell therapy, and there are a lot of challenges in having a successful CAR T-cell therapy in solid tumors."

CD70, a type II transmembrane glycoprotein, is expressed in a variety of hematologic and solid tumor cancers, including up to 80% of RCCs, and has restricted expression in normal tissue, Srour said, thus making it a promising target for CAR T therapy.

ALLO-316 also has "some unique features that might make it more attractive to treat kidney cancer," he noted. For example, to reduce the risk of graft-versus-host disease, the T-cell receptor alpha is disrupted with ALLO-316 cells. In addition, CD52 is knocked out to allow the use of ALLO-647, an anti-CD52 monoclonal antibody that depletes host T cells and improves the persistence of allogeneic CAR T cells.

For this multicenter, dose-escalation study, Srour and team looked at two conditioning regimens and four cell dose levels, ranging from 40 to 240×10⁶. Nine patients received ALLO-316 at the lowest dose level of 40×10⁶, eight received a dose level of 80×10⁶, and two patients received 120×10⁶. ALLO-316 infusions were administered 48 hours after lymphodepletion conditioning with fludarabine/cyclophosphamide, with or without ALLO-647.

The median age of participants was 62, and 84% were men. Patients were heavily pretreated, with a median of three lines of prior therapy; 73.7% received more than one checkpoint inhibitor and 52.6% received more than one tyrosine kinase inhibitor.

Safety data were comparable to that demonstrated with autologous CAR T-cell therapies. All-grade and grade 3 or higher treatment-emergent adverse effects included infusion-related reactions (5% and 0%, respectively), cytokine release syndrome (58% and 5%), neurotoxicity (68% and 11%), infection (42% and 21%), and prolonged grade 3 or higher cytopenia at day 28 (16%).

Durability of Response

Srour said that about half of the patients with CD70-positive RCC had responses that were more than 4 months, and that some patients have been able to extend response with a second infusion of the CAR T-cell product.

Haanen suggested that the limited duration of response was likely due to the use of lower doses, "but could also be due to the heterogenous expression that we see in solid cancers."

He and Srour were later asked what the minimum duration of response should be to justify the use of this therapy and to adopt it broadly.

"We have to realize we are treating patients who are at the end stage of the disease, so these are patients who are highly pretreated," he said. "Of course, what you would like to see are durable and deep responses, but this study is still at an early phase. We'll want to see if at higher doses there are more patients having a response, and especially by only selecting patients that are expressing the target [CD70]. Without expressing the target, you cannot expect any effect of the CAR T cells."

Srour agreed that the goal is to see deep and durable responses, but highlighted the fact that this was just a one-time infusion of ALLO-316.

"Hopefully, as we see with hematological malignancies, we'll see 2, 3, or 5 years," he said. "But, even if you get 6 or 8 months from one infusion, you can redo it and get another 6 or 8 months."

Comment