Research highlights from the 2025 Seattle Cellular Therapy Summit

Rosa Nadal Rios, MD, PhD, is an Associate Professor in the Division of Hematology and Oncology at Fred Hutchinson Cancer Center and the University of Washington School of Medicine. At the summit, she shares her expert insights on the evolution of cellular therapy for malignancies of the prostate, kidney, and testicular cancers.

Transcript

Disclaimer: This audio transcript has been edited for clarity and has been reviewed by the speaker.

Thank you for the introduction and for the opportunity to talk about GU malignancies and cellular therapy.

I’ll start with a brief timeline. Engineered cellular therapy dates back about 30 years, beginning with T-cell engineering at the Whitehead Institute. Preclinical data with CD19-directed T cells against Raji B-cell lymphoma followed, and by 2012, the first-in-human trials of CD19 CAR T cells were reported. Now, a decade later, we are seeing the first in-human protocols for GU malignancies, about ten years behind hematologic cancers.

Prostate Cancer

Prostate cancer is the most prevalent GU malignancy, and CAR T cells have reached important clinical milestones here. Two trials with PSMA-targeted CAR T cells have been completed. These included PSMA-TGFꞴRDN CARs, designed to resist TGF-β–mediated inhibition. In one study of 13 patients, five developed at least two CRs, including one patient with marked CAR T expansion and a dramatic PSA decline, though complicated by grade 4 CRS and sepsis. Other patients showed only modest PSA declines (~30%). A second PSCA-directed CAR T trial showed different toxicity but similar limited efficacy—no objective responses.

Correlative work showed that PSMA CAR T cells did traffic to tumors. In 7 of 9 biopsies, PSMA-TGFꞴRDN cells were detected intratumorally, associated with T-cell proliferation and activation markers, but also with mixed myeloid activation and increased inhibitory molecules. This highlights the challenges of CAR T in solid tumors: the suppressive tumor microenvironment.

Because of these limitations, PSMA/PSCA CAR development is paused, but next-generation approaches are being explored.

An alternative target is STEAP1, an androgen receptor–regulated gene highly expressed in metastatic castration-resistant prostate cancer (mCRPC), with lower expression in other normal tissues. STEAP1 plays a role in proliferation and invasion and shows more consistent positivity than PSMA. Preclinical studies showed that STEAP1 CAR T cells eradicated disseminated prostate cancer models in mice and persisted peripherally up to day 49. These findings have led to a Phase 1/2 dose-escalation and cohort study of STEAP1 CAR T cells with enzalutamide in mCRPC patients, representing one of the most exciting new protocols in prostate cancer cellular therapy.

Kidney Cancer

So moving on to kidney cancer. Clear cell renal cell carcinoma (ccRCC) presents a unique antigenic landscape: low mutational burden, HIF-driven transcription, and expression of antigens such as CAIX, VEGFR, CD70, HERV-E, AXL, ROR2, and MUC1.

One of the most promising targets is CD70, which is overexpressed in RCC. CD70/CD27L interactions normally stimulate T cells, but in tumors, CD70 expression is linked to immune suppression. Multiple groups are developing allogeneic CAR T cells targeting CD70, using healthy donor–derived T cells with gene editing to make off-the-shelf products.

The TRANSVERSE Phase 1 trial (ALLO-316) tested allogeneic CD70 CAR T cells. In 20 patients with high CD70 expression, the objective response rate was 44%, and some responses were durable. Over 50 patients have now been treated, making this one of the most clinically advanced CAR T products in kidney cancer.

Another fascinating development is the discovery of HERV-E (ERV-4) as a tumor-associated antigen in RCC. Human endogenous retroviruses (HERVs) are remnants of ancient infections, usually silenced in normal cells, but reactivated in some cancers. A Phase 1 trial of HERV-E TCR T cells in metastatic RCC showed feasibility and safety, though the overall response rate was only 7%. Correlative studies are examining infusion product composition and IL-2 kinetics to understand limited efficacy.

Testicular Cancer

Finally, in testicular cancer, CAR T cells targeting Claudin-6 (CLDN6) are being tested, with or without an RNA vaccine (CARVac) designed to amplify CAR T expansion. Early results showed ~50% response rates, including durable responses in testicular cancer, but as the trial expanded, the overall response rate declined, and the future of this program remains uncertain.

Closing

In summary, cellular therapy for GU malignancies is progressing, though challenges remain. The tumor microenvironment continues to limit efficacy in solid tumors, but advances such as STEAP1 targeting in prostate cancer, CD70-directed allogeneic CARs in RCC, and HERV-based TCR therapies show real promise. The field is now building toward the kind of breakthroughs we have already seen in hematologic cancers.

Thank you.