Picking the right target and helping recruit a wider range of anti-tumor immune cells can help improve CAR-T cell therapy against advanced prostate cancer, according to new preclinical work from Fred Hutchinson Cancer Center scientists, published in Nature Communications earlier in April. The newly developed CAR-T cells described in the study will form the basis of an early-stage clinical trial to test them in people whose late-stage prostate cancer has defied other treatments.
“This is the first time this approach has been applied to prostate cancer and in the context of engineered T-cell therapy,” said Fred Hutch prostate cancer researcher John Lee, MD, PhD, who led the study. “We showed applying this immune-boosting drug to an immunologically ‘cold’ tumor microenvironment can convert it to a hospitable, ‘warm’ environment.”
Lee’s team developed an engineered chimeric antigen receptor (or CAR) T-cell therapy directed against a molecule called STEAP1, which is expressed more uniformly across tumor cells from advanced prostate cancer than the more commonly explored target, PSMA, or prostate-specific membrane antigen. The group showed that when anti-STEAP1 CAR T cells were combined with a drug developed by collaborators at Imperial College London that focused an immune-boosting molecule within tumors, the CAR T cells could more effectively reduce prostate tumor growth and progression in preclinical models of the disease. The strategy also helped prevent the tumors from escaping immune attack by drawing in host T cells that could attack a wider range of targets.
The anti-STEAP1 CAR T cells that Lee and his team developed are already tailored for use in people. Supported by the National Cancer Institute Experimental Therapeutics Program, or NExT, the team will test their newly anti-STEAP1 CAR-T cells against metastatic, "castration-resistant" prostate cancer in a Phase 1 clinical trial slated to open in early 2024.
In the last decade, new treatments that block the androgen receptor and its downstream effects have extended the lives of men with advanced prostate cancer — but eventually metastatic prostate tumors evolve to resist these therapies. People with advanced, so-called “castration-resistant” prostate cancer desperately need therapies that can attack this disease, and Lee is hunting for them.
One avenue that Lee and other prostate cancer researchers are exploring is immunotherapy. Immunotherapies have been transforming cancer treatment: checkpoint inhibitors for once-deadly melanoma and non-small cell lung cancer, and engineered immune cells for various types of leukemia and lymphoma. Prostate cancer was the first cancer type to get a specialized immunotherapy when the cancer vaccine Provenge (sipuleucel-T) was approved to treat asymptomatic metastatic castration-resistant prostate cancer in April 2010. Lee aims to capitalize on these advances to develop new, immune-based treatments that will treat, or perhaps even cure, these deadly cancers.
He focuses on engineered immune cells known as T cells, that carry a scientist-designed molecule called a chimeric antigen receptor, or CAR, that can help them find cancer cells to kill. Memory T cells can live as long as the person carrying them — making them a potentially powerful weapon against cancer and recurrence.
“We started with the idea that we might be able to leverage the potency of memory T cells as a living drug,” Lee said.
Solid tumors like prostate cancer make it tricky for scientists to effectively deploy engineered T cells. The best CAR-T target needs to be found almost exclusively on tumor cells to minimize killing of healthy tissues and uniformly on tumor cells — to reduce the chances that tumor cells will escape the T-cell onslaught. The CAR T cells currently on the market target cells with a protein called CD19 on their surface. These CARs work against B-cell malignancies — leukemias and lymphomas — and they take advantage of the fact that only B cells carry CD19.
These kinds of targets are difficult to find on solid tumors like prostate cancer: many of the proteins they express are found elsewhere in the body, and oftentimes, even if a protein is found primarily in a tumor, many tumor cells still won’t have it.
To make Lee’s and other immunotherapy researchers’ jobs even harder, the microenvironment of solid tumors often changes to tamp down immune attack. Tumors may keep T cells out by releasing less molecules that attract them. Other immune cells that do get into the microenvironment may get “turned,” switching to a pro-tumor mode that allows them to shut down activity of T cells that do find their way into the tumor. Such tumors are termed immunologically “cold” because they prevent ignition of the inflammatory environment T cells need to do their jobs.
To develop an effective anti-prostate cancer CAR-T cell therapy, Lee needed to overcome both hurdles: find the right target, and “thaw” the tumors.
Prostate-specific membrane antigen, or PSMA, is highly expressed on prostate tumor cells, and forms the basis for a variety of diagnostic tests and treatments. Other scientists are working to develop CARs that target PSMA, but Lee’s studies suggested that prostate tumors might harbor even better CAR-T targets.
In 2018, his team found that a protein called STEAP1 is among the most highly enriched proteins on the surface of prostate adenocarcinomas, the most common type of prostate tumor. Other researchers have also linked STEAP1 to cancer, and tried to develop immunotherapies aimed at STEAP1, like the antibody-drug conjugate vandortuzumab vedotin, though none have cleared early-stage clinical trials. In the current Nature Communications study, Lee’s group, led by postdoctoral fellow Vipul Bhatia, PhD, dug deeper into STEAP1 expression in prostate tumor cells, and compared it to PSMA.
They surveyed STEAP1 on prostate tumor biopsies from men who had donated their tumor tissue through the University of Washington/Fred Hutch prostate cancer rapid autopsy program. They found that in addition to occurring at high levels on prostate tumor cells, STEAP1 was also found on a much higher proportion of prostate tumor cells than PSMA. And, when they looked at prostate tumor tissue biopsies taken from more than one metastasis in an individual patient, the researchers saw that STEAP1 was found across metastases — suggesting that many prostate tumor cells would be vulnerable to a STEAP1-targeting treatment.
CARs are a mash-up of an antibody and the molecular apparatus T cells use to detect and propagate signals through the T-cell receptor, the molecule T cells usually use to determine which cells to target. Bhatia built his new CAR using the antibody originally developed for the antibody-drug conjugate that had foundered in a Phase 1 trial, likely due to the toxicity of the drug attached to the antibody. He fused this to a second-generation CAR backbone that incorporates the latest constituents that promote T-cell persistence and activation.
The CAR that Bhatia and Lee developed allowed T cells to recognize cells that bear STEAP1 — even at very low levels, helping to increase the number of prostate tumor cells likely to be vulnerable to the therapy.
To test the new CAR T against prostate cancer, Lee and his group used patient-derived xenograft (or PDX) models, in which tissue taken from human prostate tumors is grown in mice. Bhatia injected the anti-STEAP1 CAR T cells into prostate tumors and saw significant inhibition of tumor growth over 25 days.
In a preclinical model of metastatic prostate cancer, mice that didn’t receive engineered T cells lived on average 31 days. A dose of CAR T cells delayed tumor progression and extended survival to 97 days. In a separate model of metastatic castration-resistant prostate cancer, the engineered T cells appeared to cure the mice. The team also developed mice that expressed a “humanized” version of STEAP1 to test both efficacy and safety of the strategy. In these mice, the engineered CAR T cells doubled survival time, but even though tumors initially shrank, they quickly relapsed and began to grow again. The engineered T cells didn’t appear to cause damage to other organs.
Bhatia and Lee’s investigations showed that when tumors progressed during CAR-T cell treatment, they did so by reducing STEAP1, the CAR target. They found that reducing STEAP1 also appears to help tumor cells become invisible to host T cells that don’t carry a CAR, as these cells also ramp down the molecules T-cell receptors use to detect targets.
While the CAR-T treatment was initially effective, the tumors went cold to escape it. To find a way to warm up the tumors, Lee turned to bioengineer Jun Ishihara, PhD at Imperial College London. Ishihara had developed collagen-binding domain-IL-12, or CBD-IL-12, a modified version of the immune-boosting molecule IL-12 fused to a piece of protein that binds to collagen.
“When you give this fusion protein systemically, it goes to areas of disordered vasculature where collagen is exposed — which is cancer,” Lee said.
This allows IL-12’s immune-inflaming activity to concentrate exactly where it’s needed. Bhatia tested the combination of anti-STEAP1 CAR T cells plus an intra-tumor dose of CBD-IL-12 in two PDX models of prostate cancer that respond poorly to checkpoint inhibitor therapy. (Checkpoint inhibitor therapy acts to block molecular “brakes” or inhibitors that keep T cells from attacking their targets.)
When closely examined, the injected tumors showed signs of a warmer, more immune-welcoming environment than uninjected tumors, including higher levels of the molecules involved in marking cells for T-cell attack.
In a model of metastatic prostate cancer, the combination of the engineered T cells and weekly CBD-IL-12 injections significantly delayed tumor progression and extended survival compared to either CBD-IL-12 given with unengineered T cells (“blind” to STEAP1-bearing cells) or engineered T cells alone.
Not only did the warmer tumor microenvironment help the CAR T cells act more effectively, but Bhatia found that it helped recruit host immune cells. This means that there’s a wider range of molecules being targeted by the immune system, which makes it harder for tumors to evade attack, even if they do find a way to tamp down STEAP1.
“We found that this combination is more effective in controlling the disease, but it’s not a cure-all,” Lee cautioned.
Lee and his team are gearing up for an early-stage clinical trial that will test their new CAR T cells against advanced prostate cancer. The team’s preclinical results are promising enough that the NCI is partnering with the team to get it to patients and NExT will produce the engineered CAR T cells needed.
The Phase 1 trial will test safety and some degree of efficacy of the anti-STEAP1 CAR T cells against advanced prostate cancer, though more testing is needed before a combo CBD-IL-12/CAR T strategy makes its debut in people. Lee and Bhatia’s CAR T cells incorporate leading-edge advances developed at Fred Hutch known to help make CAR-T therapy more powerful and longer lasting, including engineering T cells with an ideal percentage of memory-type T cells that can form the basis of a longer-lived response.
Lee thinks that the basic strategy described in the Nature Communications study — boosting the reach and power of CAR T cells with other molecules that recruit host T cells — could one day be adapted for other “cold” solid tumors. And his CAR T may be relevant to other tumors that are known to express STEAP1, such as Ewing sarcoma, a cancer of the soft tissue that usually arises in childhood or adolescence.
His team is also working to extend and optimize the combo approach, he said.
“We want to empower not only the CAR T cells, but also we’re trying to empower the host immune system to aid and fight against the cancer,” Lee said. “Those studies are ongoing, but they’re really promising.”
This work was supported by the Department of Defense Prostate Cancer Research Program, Swim Across America, the Pacific Northwest Prostate Cancer SPORE, the Institute for Prostate Cancer Research, a Fred Hutch/University of Washington Cancer Consortium Safeway Pilot Award, the Doris Duke Charitable Foundation, a JSPS Overseas Research Fellowship and the Prostate Cancer Foundation.
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
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