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CAR T-Cell Therapies Show Early Promise Against Advanced Prostate Cancer

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NEW YORK – Autologous CAR T-cell therapy could benefit metastatic castration-resistant prostate cancer patients, according to early research presented during the American Society of Clinical Oncology's Genitourinary Cancers Symposium last week.

Ongoing Phase I clinical trials of Poseida Therapeutics' P-PSMA-101 and Mustang Bio's MB-105 both suggested manageable safety profiles and preliminary anti-tumor activity in heavily pretreated prostate cancer patients.

While further data will be required to cement proof of the treatments' efficacy, the recent readouts are worth noting in part because developers of autologous cell therapies have historically struggled to demonstrate benefit in solid tumors. Treatments involving harvested, modified, and reinfused immune cells are now commercialized for hematologic cancers but have not shown the same benefit for solid cancers, in part because the T cells often cannot infiltrate tumor cells on the first pass and can easily become exhausted.

A number of firms have been working to address these barriers with their CAR T-cell products. San Diego-based Poseida, for instance, is taking a non-viral, transposon-based approach to engineer its autologous cell therapies. To manufacture P-PSMA-101, Poseida uses a system dubbed PiggyBac, in which it delivers a therapeutic transgene into stem cell memory T cells, shown to improve therapeutic persistence versus other T-cell types.

As Poseida CEO Eric Ostertag previously explained during an earlier readout from the ongoing P-PSMA-101 trial, CAR T-cell therapies that use viral vectors to engineer cells must activate T cells first by way of infecting it, whereas the PiggyBac technology allows Poseida to insert DNA and RNA straight into the cell.

"It is made of a very unique, non-viral transposon system … that results in a CAR T-cell product that is composed of a high percentage of stem memory T cells with the capacity to endure and proliferate within the blood stream," Susan Slovin, a medical oncologist at Memorial Sloan Kettering, said of P-PSMA-101 during her presentation of the latest data readout on Thursday. Another unique quality of the therapy, she added, is its ability to infiltrate bone, which is a common site of metastasis in mCRPC.

In Poseida's Phase I trial, 10 out of 14 evaluable patients experienced measurable declines in prostate-specific antigen levels as of the most recent data cutoff. Over one-third of the patients — 36 percent — experienced a PSA decline of 50 percent or more, and one patient experienced a complete tumor elimination that has lasted more than 10 months.

"Treatment-related adverse events did exist, but were tolerable and remediable," Slovin noted.

At trial sites where PET imaging was available, trial investigators collected PSMA data from PET scans, including FDG- and PSMA-PET, as an additional surrogate efficacy measure beyond PSA levels. Not all sites had that capability, but the investigators have pointed out a concordance between declines in PSA and PSMA levels by PET imaging in cases where this technology was available.

"This is just an interim update, [but] it showed exceptional efficacy of the product with the bone tropism at least in two patients to date," Slovin said. "At very low doses … this [treatment] induced a durable biochemical, radiochemical, radiographic, and functional complete response with significant CAR T-cell expansion."

Mustang Bio's autologous CAR T-cell therapy, which, unlike Poseida's treatment, does use a lentiviral approach to engineering cells, also showed promising activity in its own Phase I trial conducted by investigators at City of Hope. The therapy is designed to target the prostate stem cell antigen, or PSCA, and is specifically engineered for patients whose tumors express PSCA according to immunohistochemistry staining. The trial is enrolling only patients whose cancers express PSCA.

So far, 12 previously treated mCRPC patients have received MB-105, none of whom experienced grade 3 or higher cytokine release syndrome. The trial's primary aim has been to determine a maximum tolerated dose for the therapy. According to Tanya Dorff, a medical oncologist at City of Hope, who presented data from the trial at the meeting, MB-105 has shown preliminary anti-tumor effects at a dose of 100 million cells following a modified lymphodepleting chemotherapy regimen. As a next step, investigators plan to increase the dose to 300 million cells.

Among 12 patients treated, seven experienced stable disease and one patient's PSA levels declined by more than 90 percent. The trial evaluated MB-105 in patients both with and without lymphodepleting chemo, and according to Dorff, this regimen appears to be important for the CAR T-cell therapy's persistence. "Clearly, there's just less ability of the CAR T cells to expand and persist [without lymphodepletion]," she said.

In further studies of MB-105, including a planned Phase Ib trial, Dorff said that investigators hope to home in on the ideal dosing strategy to optimize efficacy and minimize toxicity. For example, cystitis, or bladder inflammation, was a dose-limiting toxicity before the investigators adjusted the dose, and Dorff said this likely resulted from PSCA expression in the bladder.

As such, the fact that PSCA can be expressed in tissues other than prostate cancer cells may be a source of on-target but off-tumor toxicity for MB-105. "That's something that we'll work hard to mitigate moving forward," she said.

If the toxicities are manageable, then on the flip side, this could also speak to the drug's broad utility. According to a statement from Mustang CEO Manuel Litchman, MB-105 could potentially benefit patients with other solid tumor types that express PSCA.