Allogeneic CAR T Therapy Controls CD70+ Clear Cell Renal Cell Carcinoma

The allogeneic chimeric antigen receptor (CAR) T-cell therapy ALLO-316 (Allogene Therapeutics) has demonstrated antitumor activity with a mangeable safety profile in participants with advanced or metastatic CD70+ clear cell renal cell carcinoma (ccRCC) enrolled in the phase 1 TRAVERSE study (NCT04696731).¹

These data were presented by Samer A. Srour, MB ChB, MS, Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine, MD Anderson Cancer Center, at the American Associated for Cancer Research (AACR) Annual Meeting 2023, held April 14-19 in Orlando, Florida.

“I am encouraged by these data highlighting the potential of an allogeneic CAR T as a new and much needed treatment modality for patients with renal cell carcinoma,” Srour said in a statement.² “Initial data from the TRAVERSE trial provides a proof-of-concept for the successful application of this novel CAR T product in the treatment of advanced renal cell carcinoma.”

TRAVERSE has enrolled 20 participants with ccRCC as of March 23, 2023; these patients had a median age of 62 years (range, 50-70) and 84% were male. Of the 19 that received ALLO-316 there was a median of 3 prior lines of therapy (range, 1-8). Participants received 40x10⁶ (n = 9), 80x106 (n = 8) or 120 x10⁶ (n = 2) CAR T-cells intravenously. There was a median of 5 days from enrollment to initiation of conditioning (range, 1-15) and median follow-up time was 7.8 months (range, 0.4-18.1).¹

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Most patients (58%) had cytokine release syndrome (CRS) of low grade except for 1 case of grade 3 CRS.¹ There were no observed cases of graft-versus-host disease (GvHD) or immune effector cell-associated neurotoxicity syndrome. Investigators identified a single dose-limiting toxicity of grade 3 type 2 autoimmune hepatitis in a patient treated at dose level 2, but maximum tolerated dose (MTD) has not yet been reached.

John Haanen, MD, PhD, Professor Translational immunotherapy of cancer, Leiden University Medical Center, and head, Division of Medical Oncology, The Netherlands Cancer Institute, also presented on the data, saying “When we look at the antitumor activity, we can say for the total group it was modest, but it was probably due to the fact that there were patients included with no expression of the target. Of course, that was seen afterwards, but what we know now is that it's important to have some expression of CD70 and I think a patient without that expression should not be treated with a targeted agent like ALLO-316."¹

In 18 patients evaluable for efficacy, Srour and colleagues found that the best overall response (OR) at all time points was partial response (PR), of which there were 3 confirmed cases at follow-up visits. The OR rate (ORR) was 17% and the disease control rate (DCR) was 89%. Specifically, the ORR was 30% in patients with confirmed CD70+ tumors (33% in those with unconfirmed tumors) and the DCR was 100% in this subgroup. Additionally, investigators noted high CAR T-cell expansion in peripheral blood (median Cmax > 35,000 copies/μg) and high vector copy numbers in 3 available tumor aspirates.¹

ALLO-316 is a CD70-targeted allogeneic CAR T-cell developed with the use of TALEN® gene editing to knock out T-cell receptor α constant gene to reduce the risk of GVHD. The therapy also knocks out the CD52 gene to allow the use of Allogene’s humanized, CD52-targeted monoclonal antibody ALLO-647 to deplete host T-cells without affecting the CAR T-cells.

The first-in-human, open-label, multicenter, single-arm, dose-escalation TRAVERSE study seeks to identify an MTD of ALLO-316 after conditioning with fludarabine/cyclophosphamide with or without ALLO-647 as well as the incidence rate for DLTs in the first 28 days after infusion. Participants must have advanced or metastatic ccRCCwith at least 1 measurable lesion and ECOG Performance Status of 0 or 1 after prior treatment with an immune checkpoint inhibitor and a vascular endothelial growth-factor-targeted therapy.

“In conclusion, RCC shows particularly high expression of CD70 which is associated with very poor outcome, and I think CD70 is a very interesting target for CAR-T therapy... I think it’s going to be very interesting to see what happens with higher doses,” Haanen concluded.¹ So, the question now is, do we need allogeneic or autologous CAR T-cells, at the moment, we don’t know, for the treatment of solid cancers? I think the lack of durability for responses that we see in this study could be due to the fact that we are at low doses, but could also be due to the heterogeneous expression that we see in solid cancers, we don't know if it’s the result of the elimination of the ALLO-316 CAR T-cells or even the anti-CD52 antibody which could hamper epitope spreading.”

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REFERENCES

1. Srour S, Kotecha R, Curti B, et al. A phase 1 multicenter study (TRAVERSE) evaluating the safety and efficacy of ALLO-316 following conditioning regimen in pts with advanced or metastatic clear cell renal cell carcinoma (ccRCC). Presented at: AACR Annual Meeting 2023, April 14-19; Orlando, Florida. Abstract #CT011
2. Allogene Therapeutics Presents Interim Phase 1 Data on ALLO-316 in Renal Cell Carcinoma at the American Association of Cancer Research (AACR) Annual Meeting. News release. Allogene Therapeutics. April 17, 2023. https://www.globenewswire.com/news-release/2023/04/17/2648154/0/en/Allogene-Therapeutics-Presents-Interim-Phase-1-Data-on-ALLO-316-in-Renal-Cell-Carcinoma-at-the-American-Association-of-Cancer-Research-AACR-Annual-Meeting.html