Trial of CAR-T for prostate cancer takes steps toward ‘potentially curative’ therapy
Click Here to Manage Email Alerts
Chimeric antigen receptor T-cell therapy exhibited activity with minimal adverse effects for men with advanced prostate cancer, findings of a first-in-human trial showed.
Researchers used a CAR T-cell therapy developed at City of Hope to treat 14 men with metastatic castration-resistant prostate cancer and prostate stem-cell antigen (PSCA) expression
Study participants received a single infusion of 100 million CAR T cells.
Safety and dose-limiting toxicities served as the study’s primary endpoints.
Four patients experienced reductions in PSA levels of at least 30%. However, researchers reported “limited persistence” of CAR T cells beyond 28 days after infusion.
Five men developed grade 1 or grade 2 cytokine release syndrome.
“We learned a lot and, with each CAR T-cell trial that goes on in prostate [cancer], we are learning more,” Tanya Dorff, MD, chief of the genitourinary disease program and professor in the department of medical oncology and therapeutics research at City of Hope, told Healio. “We’ve partnered with a few other institutions doing studies in prostate [cancer] to increase the power of our ability to observe what makes the patient respond. I really believe these are steps forward toward a treatment that is potentially curative.”
Healio spoke with Dorff about the findings and the next steps in research.
Healio: Can you provide context for the challenges associated with using immunotherapy to treat prostate cancer?
Dorff: We’ve had multiple negative phase 3 clinical trials, including trials of the GVAX cancer vaccine (HealthTree Inc.) and ipilimumab (Yervoy, Bristol Myers Squibb). The only immunotherapy that made it to approval was sipuleucel-T (Provenge, Dendreon Pharmaceuticals). A lot of biologic work has been done to understand the challenges. We see a lack of T-cell infiltration — it’s an immune desert. The mechanisms of that are less well understood. The heterogeneity of it is just beginning to be better described, along with the molecular underpinnings. We know we need to do something dramatic to get the immune system engaged and be able to get into the prostate cancer microenvironment. There are a lot of suppressive elements in that microenvironment so, even if the immune system does recognize and get in there, it is often shut down.
Healio: Why did you conduct this study?
Dorff: We were motivated by the failures of prior simpler, less potent immunotherapies. We know there are antigens unique to prostate cancer that should leverage themselves to be addressed in a way that activates the immune system against these specific antigens. City of Hope has a great history with CAR T-cell therapy and a lot of scientists working on it, so it felt like the right set of conditions to do a phase 1 trial.
Healio: How did you conduct the study?
Dorff: We started by prescreening patients for PSCA, a relatively new target. We thought it had some favorable characteristics as a target for immunotherapy, so we wanted to make sure patients enrolling had PSCA expression in their tumors.
For our first three patients, we weren’t sure we needed lymphodepletion chemotherapy. We also wanted to see what the T cells would do on their own. CAR T cells alone showed mild activity but not what we were looking for, so we added lymphodepletion chemotherapy to CAR T cells in the next group we treated. In a third group, we were going to escalate the CAR T cell dose but could not due to off-tumor toxicity in the bladder. Instead, we modified the chemotherapy dose and were able to safely administer it without any dose-limiting toxicity. We saw activity but not enough, so we decided to end this study and open a new one with a novel dosing strategy.
Once the patient had their CAR T-cells produced, we did a biopsy of the tumor site. We matched that with a biopsy at day 28 of the same site, so we could look at the immune environment before and after. We also collected blood frequently to look at cytokines and CAR T-cell expansion.
Healio: What did you find?
Dorff: We didn’t get the expansion of CAR T cells we needed without lymphodepletion chemotherapy.
We also found a high level of CAR T-cell activity in some patients, with one experiencing a dramatic response lasting months. However, the cells didn’t persist long enough to maintain their effectiveness. We will need further research into strategies for increasing persistence. An important third finding is that CAR T-cell therapy can be administered safely in prostate cancer, without the severe toxicities seen in previous studies.
Healio: What are the next steps in research?
Dorff: Our phase 1b trial is ongoing. The strategies we will evaluate are designed to maximize efficacy. We will be adding treatments on top of or before CAR-T to see if we can optimally prepare the tumor microenvironment so that when the CAR T cells get in there, they can kill the cancer. We will have several cohorts looking at different ways of doing that.
Reference:
For more information:
Tanya Dorff, MD, can be reached at tdorff@coh.org.
Collapse
Healio Interviews
Click Here to Manage Email Alerts