Immunotherapy is being investigated more and more for the treatment of prostate cancer, and although not many of these therapies are currently FDA-approved, mounting data shows promise.
At the 15th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies, Susan F. Slovin, MD, PhD, gave a presentation on immunotherapy in advanced prostate cancer,1 reiterating the significant impact that this mode of treatment has had on patients with this disease. In the following interview, she discusses the main points of her talk and what is to come in this space. Slovin is a medical oncologist at the Memorial Sloan Kettering Cancer Center in New York City, New York.
We are seeing a tremendous amount of interest in using chimeric antigen receptor T [CAR T] cells as an immune approach in prostate cancer. A lot of what we've done has been predicated on various immunologic approaches that included carbohydrate, DNA, and naked DNA vaccines, as well as antibody drug conjugates directed against a variety of cell surface targets. What is very challenging about any sort of immunotherapy, and in particular the checkpoint inhibitors, is that you need to get the treating product or the immune cells into the tumor microenvironment, which in the case of prostate cancer, happens to be the bone. So, among the challenges that everybody's looked at, with regard to chimeric antigen receptor T cells, or armored CAR T cells, which we like to call them sometimes, is that they need to be stable. They are not necessarily off the shelf, because they are an autologous product, but they also have to migrate to the site of the tumor, and to persist at the site of the tumor where they can have an anti-tumor response. Similar to the experience of others, we've always been faced with the fact that we used to use retroviral vectors to generate the final CAR product and that there are challenges to in how to maximize the in vivo efficacy of the CAR T cell. The retroviral vector transduced final CAR T cell product was often unstable, reaching the tumor-stromal interface, yet not moving beyond into the tumor. A preparative regimen is needed to remove any inhibitory immune cells, ie, regulatory T cells (Tregs) that may contribute to a hostile tumor microenvironment, thereby providing an intratumoral milieu that blocks immune cell penetration. Other challenges to this therapy include knowing the affinity of the CAR T cell for the antigen in question.Clearly, prostate-specific membrane antigen, or PSMA, has been a focal target for a variety of different approaches, including immunological approaches with vaccines and antibody-drug conjugates in addition to CAR T cells, and more recently, a theranostic approach with 177-lutetium PSMA-617. What's unusual about the construct of our CAR T cell is that it is not based on a retroviral vector; it is a non-viral transposon system (piggyBac®) that results in a CAR T product comprised of a high percentage of T stem cell memory cells. Genes are inserted encoding a PSMA-targeted Centyrin CAR with an iCasp9-based safely switch and DHFR to purify CAR T Cells.These T stem cell memory cells have bone marrow homing capability that may be particularly relevant to bone tropic tumors, such as prostate cancer. Importantly, the benefit of this platform is that it will provide immunologic memory such that the CAR T cells will persist at the site of tumor, leading to more time for the cell to elicit an antitumor response. This PSMA 101 platform has resulted in an ongoing phase 1, dose-escalating multicenter trial that seeks to determine safety and tolerability of the CAR T cell. Patients receive lympho-depleting chemotherapy of standard regimen fludarabine and cyclophosphamide, followed 72 hours later by the infusion of the autologous CAR T cells. The infusion is well tolerated with the expectation of grade I/II cytokine-release syndrome. The bottom line to date is these cells can get to the site of tumor, proliferate, leading to the detection of the CAR T cells within the site of the tumor.
I would like to cite at least 2 cases that we've seen to date. The first is a patient with a significant family history of prostate cancer. He had [undergone] prior prostatectomy, radiation, palliative radiation to a site in bone, and had a pre-treatment PSA of 33 [ng/mL]. He went through lympho-depleting therapy, received autologous PSMA CAR T cells at .25 x106/kg dose within hospital monitoring for 14 days. He underwent baseline bone, CT, FDG and PSMA PET scans before treatment and at weeks 4 and 12 post treatment and every 3 months thereafter. Having an imaging biomarker correlate is important for assessment of response as is PSA. There was significant concordance between the FDG and PSMA PET scans and the bone scan before treatment. What was very interesting is that at the 4-week mark, we did additional imaging with the PSMA PET scan and found that at prior sites of known high SUV disease, there was almost a >90% decline in the SUV at the sites that we had known about. We elected to biopsy the bone site that showed a decrease in the SUV on the PSMA PET scan. This showed no evidence of tumor cells but indicated bone remodeling. IHC for immune cells showed the presence of CD4+ and CD8+ T cells. We sent a sample to the sponsor, and via PCR, they were able to demonstrate that the CAR T cells were within the now treated prior tumor microenvironment within the bone. To my knowledge, this is the first time that we've ever been able to show this particular response, ie changes in bone scan, FDG and PSMA PET scan along with the absence of disease by biopsy at a site of known activity. His PSA decline to less than 0.11 [ng/mL], and this month it’s been 1 year since his initial treatment. All his imaging remained unchanged for approximately the last 10 months until his PSA started to rise, now at 23 with recurrent disease on PSMA PET scan in bilateral hips with no change in bone or CT scans. The patient has requested retreatment which is planned within the next several weeks.
Another patient who had presented with very significant bone disease at diagnosis, unlike the former gentleman, had a partial response with some marked SUV diminution at different sites on PSMA PET scan; bone biopsy also revealed the presence of CAR T cells. This platform to date is safe platform; additional patients have also had profound declines in PSA and stable disease.
I think it really depends on the extent of the disease. We know that prostate cancer has responded suboptimally to immune-based approaches unless there is an agnostic indication for immunotherapy, such as a microsatellite high unstable. That's where pembrolizumab [Keytruda] has been approved with responses. Combinatorial trials using checkpoint inhibitors with chemotherapy have not been particularly effective My recommendation for any practitioner is to be very savvy about the treatment-associated side effects that can occur early or even late with immune checkpoint inhibitors. The checkpoint inhibitors in urologic cancers such as renal cell and urothelial cancers have been practice changing, however, one needs to be circumspect about the potential toxicities that are associated with these drugs and to be especially vigilant on the clinical status of the patient who will be receiving these drugs.
The field of theranostics is certainly taking off at a very rapid gait. We have the 177-lutetium PSMA-617 at the FDA right now and its approval will be practice altering for many but not all patients, hence the need for other approaches. My biggest concern here is [that] sometimes when a drug is newly FDA approved, or we see a signal, everybody wants to be treated with the same drug with the expectation that the therapy is definitely going to work for everyone. I think the most important takeaway is that the new drugs that are out there [are] not for everybody.Another area that's really burgeoning is genomic profiling and biomarkers. Those are the hot areas of research. They are especially challenging as serial specimens need to be collected, banked then analyzed with subsequent assessment to determine the surrogacy of the biomarker within a particular disease state.
Immunotherapy is alive and well. People's concepts of immunotherapy seem to be checkpoint inhibitor centric. Immunotherapy is not just about checkpoint inhibitors. I've been in this field a very long time, so I've seen immune therapies come and go. There's no question that the checkpoint inhibitors have made a significant contribution to the care of patients with a variety of genitourinary malignancies, but that doesn't mean that autologous cellular therapies can be equally helpful. Sipuleucel-T [Provenge®], which is the first autologous cellular therapy, albeit probably a dendritic therapy to be FDA approved and showed a survival benefit, never had the response robustness that we're seeing with the checkpoint inhibitors and perhaps even with the CARs. It does impact to some extent on the tumor microenvironment but does not provide the kind of antitumor response that patients expect. Who uses it? Urologists like to use it as a temporizing measure with the hope that in cases of asymptomatic or minimally symptomatic patients with metastatic castration-resistant prostate cancer, it may have some benefit in delaying disease progression which is a reasonable goal.When a treatment choice is sometimes unclear, I tell both patients and colleagues that a clinical trial is always a very reasonable option and should be ranked high for their consideration
1. Slovin SF. Immunotherapy in advanced prostate cancer. Presented at: 15th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies; New York City, New York. March 11-12