Investigators Look Beyond Immune Checkpoint Inhibitors to Chase Moving Targets in Prostate Cancer

Immune checkpoint inhibitors represent only one area of effective therapy for patients with advanced prostate cancer, but they are not “be all, end all” of immunotherapy options, according to Susan F. Slovin, MD, PhD.

In a poll ahead of her presentation at the 15th Annual Interdisciplinary Prostate Cancer Congress^® and Other Genitourinary Malignancies, Slovin asked the audience their preferred antigen-targeted therapy for patients with advanced disease. In response, 50% of participants at the meeting said they would choose an antigen-drug conjugate with a chemotherapy payload.¹

Slovin, who is associate vice chair of the Academic Administration in the Department of Medicine at Memorial Sloan Kettering Cancer Center, in New York, New York, commented that these results might stem from the allure of targeting prostate-specific membrane antigen (PSMA) and the latest data on the Lutetium-177 (Lutathera), a radioligand therapy that delivers β-particle radiation to PSMA-expressing cells and the surrounding microenvironment.² “That is not pure immunotherapy, and a lot of [individuals] are under the misapprehension that it is,” Slovin said. “Lutetium-177 is a targeted therapy [and it] may have some immune mechanism and it gets internalized into the cell, but it [is not] what we call immunotherapy.”

In terms of what does constitute immunotherapy in prostate cancer, Slovin noted that identifying a target is only one step of the process. Overcoming resistance to engage it representes the greatest challenge in the field. “There are a lot of different antigens on the surface of tumor cells in prostate cancer, but are all of them targetable? Is their expression stable or is it constantly ephemeral? If you are going to target a tumor antigen, [you need to] find one where an antitumor effect [is possible]. It’s hard to know the relevance of a particular molecule just by virtue of it being there, we don’t really know if it’s targetable.”

Tumor Antigen Not Equal to the TME

Prostate cancer is often referred to as a “bland” or “cold” disease, Slovin explained; however, a lack of expression on immune cells is only the tip of the iceberg from discovering and acting upon targets. Several immunosuppressive factors that within the tumor microenvironment prevent the transformation to a “hot” or “inflamed” environment, including cancer-associated fibroblasts, T regulatory cells, and inhibitory molecules such as adenosine.

The presence of CD8-positive T cells in the tumor microenvironment has been described in 3 scenarios: desert, in which T cells are absent from the tumor and its periphery; excluded, in which the T cells have accumulated but do not efficiently infiltrate the tumor; and inflamed, in which the T cells infiltrate but their effects are inhibited.³ Approaches to overcome resistance to facilitate immune infiltration including oncolytic viruses which promote T-cell priming, adoptive cellular therapies that promote T-cell expansion, and TFGβ inhibitors which promote T-cell trafficking and infiltration.^1,3

“Tumor cells are covered with a variety of different cells [such as] macrophages, inhibitory cytokines, inhibitory T cells, adenosine—how do you get through? It’s not easy,” Slovin said. “For each aspect, if you are trying to develop strategies, each type of approach is going to be correlated with trying to get into the tumor cells through those inhibitory molecules or cells or cytokines. [For example,] vaccines work by increasing antigen presenting cells and trying to get the T cells to see [and learn] the molecule, and then go out and kill adoptive T cell therapy.”

Slovin added that tactics such as checkpoint blockade have demonstrated some antitumor effects in patients with microsatellite instability high disease, but in general the response has been very suboptimal. Most recently, results of the phase 2 IMPACT (NCT03570619), which evaluated dual checkpoint inhibition with nivolumab (Opdivio) and ipilimumab (Yervoy) in patients with CDK12 inactivation or mutated metastatic castration resistant prostate cancer showed that only 14.2% (n = 4/28) of patients had a reduction of prostate-specific antigen (PSA) of at least 50%. Further, results showed that 6 patients (21.4%) had a 10-fold rapid increase in PSA over baseline.⁴

“[These data are] interesting because despite the information presented [in Cell on the prevalence of CDK12], which indicated that these tumors were highly responsive to nivolumab or [pembrolizumab (Keytruda)], investigators of the phase 2 trial didn’t see any signal,” Slovin said. “[It was] very surprising.”

Leveraging Lessons Learned From PSMA

Overexpressed in resistant disease, PSMA represents a favorable targeted for both immune and radiographic therapies for prostate cancer. The focus of development in immunotherapies targeted PSMA are bispecific T-cell engagers (BiTEs) and chimeric antigen receptor (CAR) T-cell therapies. However, investigators are looking to build on the efficacy observed with such therapies leveraging PSMA to develop novel approaches.

BiTEs

BiTE therapies are designed with 2 flexibly linked, single-chain antibodies that simultaneously bind to targets on cancer cells and CD3 expressed on T cells which results in T-cell infiltration, activation, cytokine production, and induced apoptosis.^1,5 “What’s interesting about [BiTEs] is that it’s an off-the-shelf product—you don’t have to custom tailor it or [initiate] leukapheresis,” Slovin said, adding that the product also has sustained activation.

Following the success of AMG 160, targeting PSMA in mCRPC, investigators set out to explore targets such as delta-like ligand 3 (DLL3).^5,6

At the 2022 Genitourinary Cancers Symposium, investigators presented an open phase 1b study (NCT04702737) on the novel half-life extender BiTE therapy tarlatamab. The study investigators will evaluate the safety and tolerability of the agent in patients with neuroendocrine prostate cancer, a disease with no standard treatment and poor prognosis. Tarlatamab targets DLL3, which is expressed on approximately 77% of neuroendocrine prostate cancer tumors.⁶

“A lot of the problems with BiTEs is that they are small molecules, and in peripheral circulation, they actually can be cleared by the kidney,” Slovin said. “One of the problems, of course, is maintaining durability of these molecules so that they can activate and proliferate and have antitumor effects. The molecule is changed to add an FC region, which is literally the tail, [and] that gives stability and longevity to the molecule.”

Patients with metastatic de novo or treatment emergent neuroendocrine prostate cancer who had disease progression following at least 1 line of prior therapy are eligible for enrollment to the study.⁶

CAR T-Cell Therapies

Slovin is investigating new approaches to the leveraging CAR T-cell therapies targeting PSMA with the novel product P-PSMA-101 in a phase 1 trial (NCT04249947). The therapy is manufactured using a nonviral transposon system resulting in a high percentage of stem-cell memory T cells, which engraft in bone marrow and are a key to CAR T-cell therapy success.⁷

As of December 31, 2021, cutoff, 14 patients had received a single infusion of P-PSMA-101 ranging from 0.25 x 10⁶ to 2.0 x 10⁶ T cells. The median age was 71 years (range, 57-79). PSA response of at least 30% was observed in 6 patients (42.9%) and PSA response of at least 50% was observed in 5 patients (35.7%). In total 10 patients (71%) had PSA decrease of any level.⁷

“CAR T-cell therapies that have troposm for bone-predominany tumors have therapeutic potential,” Slovin noted of the results.

In her conclusions, Slovin noted that immunotherapy is alive and well in prostate cancer, but that more insight to the mechanisms of cell-to-cell and cell-to-stromal interactions require more focus. Additionally, she emphasized the importance of biopsy, genomic profiling, and the use of companion imaging diagnostics for patients. “You need companion imaging—it is extremely important because it is giving you an a window into where the activity lies or no longer lies,” she said.

References

1. Slovin SF. Immunotherapy for advanced prostate cancer. Presented at: 15th Annual Interdisciplinary Prostate Cancer® and other GU Malignancies Congress. March 11-12, 2022. New York, NY.
2. Sartor O, de Bono J, Chi Kn, et al; VISION Investigators. Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322
3. Liu YT, Sun ZJ. Turning cold tumors into hot tumors by improving T-cell infiltration. Theranostics. 2021;11(11):5365-5386. doi:10.7150/thno.58390
4. Alva AS, Li J, Chou J, et al. Phase 2 trial of immunotherapy in tumors with CDK12 inactivation (IMPACT): results from cohort A of patients (pts) with metastatic castration resistant prostate cancer (mCRPC) receiving dual immune checkpoint inhibition (ICI). J Clin Oncol. 2022;40(suppl 6):103. doi:10.1200/JCO.2022.40.6_suppl.103
5. Subudhi SK, Siddiqui BA, Maly JJ, et al. Safety and efficacy of AMG 160, a half-life extended BiTE immune therapy targeting prostate-specific membrane antigen (PSMA), and other therapies for metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2021;39(suppl 15):TPS5088. doi:10.1200/JCO.2021.39.15_suppl.TPS5088
6. Aggarwal RR, Rottey S, Aparicio A, et al. Phase 1b study of tarlatamab, a half-life extended bispecific T-cell engager (HLE BiTE immune therapy) targeting DLL3, in de novo or treatment emergent neuroendocrine prostate cancer (NEPC). J Clin Oncol. 2022;40(suppl 6):TPS197. doi:10.1200/JCO.2022.40.6_suppl.TPS197
7. Slovin SF, Dorff TB, Falchook GS, et al. Phase 1 study of P-PSMA-101 CAR-T cells in patients with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2022;40(suppl 6):98. doi:10.1200/JCO.2022.40.6_suppl.098