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NASHVILLE, Tenn. -- Chimeric antigen receptor (CAR) T-cell therapy has the potential to become standard-of-care therapy for renal cell carcinoma (RCC) that does not respond to current therapies, an RCC specialist said here.

CAR T-cell therapy is not yet ready for clinical practice, but enrolling patients in the growing number of clinical trials can help move the therapy closer to that goal, said Michael Hurwitz, MD, of Yale Cancer Center in New Haven, Connecticut, during the International Kidney Cancer Symposium.

"I would say that this is exciting, it's interesting, but we're not there yet," said Hurwitz. "Just like the end of every Hollywood blockbuster, when the bad guy is dying, or about to fall in the lava or something, and his hand is waving, and it's like this is just the beginning. I think this is kind of just the beginning because there are many, many different technologies we can use to make these T cells much more effective."

Multiple clinical trials of CAR T-cell therapy for advanced solid tumors are in various stages of conduct. The trials are evaluating T-cell constructs that have a variety of targets. Hurwitz focused on studies of T cells targeting CD70 and carbonic anhydrase IX (CAIX), which have accumulated the most results to date.

CAIX is highly expressed in kidney cancer but also expressed at lower levels in biliary epithelium. About a decade ago, a small trial of became something of a cautionary tale about CAR T-cell therapeutic development, said Hurwitz. Four of the first eight patients treated had dose-limiting liver toxicity. A third four-patient cohort received anti-CAIX antibody prior to CAR T-cell therapy to address liver toxicity, but no objective responses occurred.

"This is a very old trial and there were a lot of other issues with the actual CARs, but this is a very important issue, what we call on-target/off-tumor effect," said Hurwitz. "There are various names for it, but what it means is that you have to pick your target incredibly well. CD70 is probably a better target for a lot of reasons."

As an example, he described a of 13 patients with advanced clear cell (cc)RCC treated at four different dose levels with allogeneic CRISPR-Cas9-engineered CAR T cells. The CRISPR-modified cells from healthy donors greatly reduced the time required to administer the therapy to patients. Being from healthy donors, the cells had an intact immune system, and the technique produced an abundance of cells in a short period of time.

The efficacy was modest, one partial response and nine patients with stable disease, including four patients who remained stable at 4 months. Response duration was modest, but the treatment was well tolerated, said Hurwitz. About 80% of the patients developed cytokine release syndrome (CRS), but the condition was mostly grade 1/2.

Earlier this year, investigators reported initial results from a phase I study evaluating a different construct of allogeneic CAR T cells targeting CD70 in advanced/metastatic ccRCC. The ALLO-316 therapy targets CD70, but by means of gene editing, investigators knocked out T-cell receptors to reduce the risk of graft-versus-host disease. Additionally, they knocked out the CD52 gene, allowing administration of an anti-CD52 antibody to deplete host T cells without affecting the allogeneic CAR T cells.

Subsequently, 11 of 19 patients developed CRS, but only one case reached grade 3 severity. Severe neurotoxicity or infection also was uncommon. The overall response rate was 17%, but the subgroup of patients with CD70-positive tumors had a 30% response rate and 100% disease control rate.

"It's a pretty impressive result," said Hurwitz. "We don't know the duration of response but it appears to be significant."

Follow-up showed that the CAR T cells persisted out to 70 or 80 days. Investigators also found that infusion of the allogeneic CAR T cells upregulated CD70, which allowed T-cell responses to persist. Eventually, anti-CD70 cells disappeared and normal T cells returned.

"There are a number of key challenges with solid tumors in general that are going to make things a lot harder than with liquid tumors," said Hurwitz. "It's hard to get these T cells to persist. Solid tumors, of course, can lose any antigen, so that makes it really hard to kill off a tumor that way. The microenvironment is very [toxic], and it's very hard to infiltrate a solid tumor."

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