Chimeric antigen receptor T cell therapy in prostate cancer: racing to prime time

Introduction

While localized prostate cancer is often associated with a favorable prognosis, metastatic prostate cancer is considered incurable and is associated with diminished quality of life along with significant morbidity (1). The disease eventually evolves into castration-resistant prostate cancer (CRPC), for which current treatments such as chemotherapy are associated with significant toxicities and ultimately, multi-drug resistance.

Initial therapy for metastatic prostate cancer is comprised of conventional androgen deprivation therapy (ADT), which is standard medical care for patients and often combined with additional systemic therapies such as docetaxel and androgen receptor pathway inhibitors; however, castration resistance eventually emerges.

Over the past two decades, the field has seen significant advancements in the biologic understanding and treatment of metastatic prostate cancer. In the United States, nine new agents have been approved for treatment of CRPC, including next-generation anti-androgens, chemotherapeutic drugs, radiopharmaceuticals, and tumor vaccines (2). Among them, Sipuleucel-T, a vaccine therapy that targets prostatic acid phosphatase, received approval in 2010 for patients who are asymptomatic or have minimal symptoms based on the IMPACT trial (3). More recently, the PSMAfore trial demonstrated that lutetium-177-PSMA-617 extended radiographic progression-free survival when compared to switching the androgen receptor pathway inhibitor therapy in patients with CRPC who never received treatment with chemotherapy (4). However, immunotherapy in general including other vaccine-based strategies and immune checkpoint inhibition, has shown only modest clinical outcomes (5-7). This is likely due to an immunologically cold prostate cancer microenvironment characterized by strong immunosuppression and a low mutational burden (8,9). The creation of genetically modified T cells capable of bypassing this proposed immune tolerance would mark a significant breakthrough.

Chimeric antigen receptor (CAR) T cell therapy

CAR T cell therapy involves the genetic modification of a patient’s T cells to present CAR on their surface, enabling the targeted recognition and elimination of malignant cells (10). In hematologic malignancies, CAR T cell therapy has demonstrated impressive clinical efficacy including durable remission. However, there have been significant challenges in solid tumors, likely due to suppression of CAR T cell activity by a highly immunosuppressive milieu (11). Other challenges include heterogenous antigen expression, an inability of T-cells to successfully infiltrate the tumor, limited persistence, and suboptimal trafficking (12). Prostate cancer generally expresses well-described tumor-associated antigens (TAAs) such as the prostate stem cell antigen (PSCA), the prostate-specific membrane antigen (PSMA), and the epidermal growth factor receptor (EGFR). TAA-targeting CARs have shown encouraging results in pre-clinical studies and early phase trials (13). For example, a phase 1 study of an experimental autologous PSCA-targeted GoCAR-T^® cell therapy incorporating an inducible MyD88/CD40 ON-switch activated by dimerizer rimiducid. In this study, BPX-601 cells expanded in the peripheral blood of all participants, reaching an initial peak within 14 days following infusion. Furthermore, the BPX-601 cells remained detectable in peripheral blood of participants with metastatic pancreatic cancer and CRPC up to 250 days after receipt (14).

PSCA-CAR T cell therapy

The study by Dorff et al. titled “PSCA-CAR T cell therapy in metastatic castration-resistant prostate cancer: a phase 1 trial” (NCT03873805) sought to assess safety and bioactivity of PSCA-targeted T cells in patients with CRPC (15). Preclinical studies utilizing xenograft and syngeneic tumor models have shown that PSCA-directed CAR T cells utilizing 4-1BB co-stimulation are both safe and effective for the eradication of metastatic bone disease (16,17).

Based on this data, a phase 1 open-label dose-escalation study was opened in August 2019. Dose level (DL) cohorts included DL1 with 100 million (M) PSCA CAR T cells (n=3), DL2 with fludarabine and cyclophosphamide (Flu/Cy) and 100 M PSCA CAR T cells (n=6), and DL3 with reduced dose Flu/Cy and 100 M PSCA CAR T cells (n=5). Fifty-eight patients were consented, 22 patients were enrolled and underwent leukapheresis, and ultimately 14 patients went on to receive CAR T cell infusion. Patient eligibility included a diagnosis of CRPC, an Eastern Cooperative Oncology Group performance status of 0–2, documented PSCA-positive tumors as assessed by City of Hope Pathology Care, and progression of disease during treatment of at least one advanced androgen receptor pathway inhibitor. Prior chemotherapy was allowed but not required, and 67% of patients received both prior docetaxel and cabazitaxel, indicating a heavily pretreated cohort. Seventy-five percent of patients were White, and 25% of patients were Black. Twenty-five percent of patients had visceral metastases at time of enrollment. Of the enrolled subjects, the median prostate-specific antigen (PSA) was 16.5, 88.0, and 235.3 ng/mL in DL1, DL2, and DL3, respectively.

The primary endpoints of this study were safety and incidence of dose-limiting toxicities (DLTs). The secondary endpoints were proliferation and persistence of CAR T cells to 28 days following infusion, disease response [described as PSA decline and Response Evaluation Criteria in Solid Tumors (RECIST)], and survival which was defined by percent of patients living at 6 months. There were no DLTs observed in the first three patients treated using DL1 (without lymphodepletion). The DL2 group reported two DLTs—both non-infectious cystitis. A DL3 was designed with a reduced dose of lymphodepletion chemotherapy cyclophosphamide (300 mg/m² from 500 mg/m²) along with mandatory mensa. In this group, no DLTs were observed in all five participants and the maximum grade of cystitis reported was grade 2. Cytokine release syndrome (CRS) of grade 1 or 2 occurred in 5 of the 14 patients: 1 reported at DL1 (33%), 2 reported at DL2 (33%), and 2 reported at DL3 (40%).

Along with a favorable safety profile, the study showed promising signs of efficacy in this heavily pretreated cohort. Four of the 14 participants experienced PSA declines greater than 30% with one individual maintaining a PSA decline of more than 30% beyond 28 days. Rate of stable disease by RECIST was 0%, 67%, and 60%; and 6-month survival rate was 33%, 67%, and 40%, in DL1, DL2, and DL3, respectively.

Challenges and future directions

CAR T cell persistence

Evaluation of CAR T cell persistence demonstrated limited cells beyond 28 days post-infusion and an absence of CAR T cell persistence coincided with a failure to observe a sustained remission. Factors associated with CAR T cell persistence include the T cell construct and the extent of lymphodepletion. Use of other constructs has been attempted in prostate cancer including a dominant negative transforming growth factor-β (TGF-β) in the context of a PSMA CAR T cell where two patients maintained measurable persistence in peripheral blood for more than 200 days following infusion (13). However, the treatment was associated with significant toxicity. Other current strategies to improve CAR T cell therapeutic effect include integrating multiple co-stimulatory signals, the use of pluripotent stem cells, and CAR ligand-targeting vaccines (18).

Lymphodepletion is an essential component to therapy while balancing the associated toxicities with various regimens. In the study by Narayan et al. (13), lymphodepletion led to increased rate of DLTs. In the study by Dorff et al., despite minimal differences between level DL2 and DL3 concerning CAR T cell expansion in the peripheral blood, reduced lymphodepletion was found to be associated with fewer CRS-related and off-tumor toxicities. Given the essential role of lymphodepletion in CAR T cell therapy, a key area of future research will focus on identifying the optimal lymphodepletion regimen that modulates the tumor immune microenvironment to facilitate effective CAR T cell expansion while minimizing DLTs.

Enrollment bias

One key limitation that may yield enrollment bias in future studies is the length of time required for manufacturing product and other barriers prior to infusion. A high drop-out rate was observed in this trial which the authors attributed to protocol-mandated holds, delays in confirmatory PSCA staining, and regulatory approval for utilization outside of approved criteria. The median duration from day of leukapheresis to day of infusion was 73 days in the study cohort. This extended process may have ultimately prevented the participation of patients with rapidly progressing disease or marginal performance status, thereby selecting for more fit patients to receive experimental treatment. This process should be streamlined for phase 2 trials to ensure the cohort mirrors that of the target treatment population.

Combinatorial strategies with immunotherapy

Pre-clinical and clinical data in other solid tumor malignancies have shown that CAR T cells experience functional exhaustion when faced with large tumor burdens due to inhibitory signaling from programmed death 1 (PD-1) and programmed death 1 ligand (PD-L1). Cell intrinsic and extrinsic methods have been described to overcome this limitation. Cell intrinsic method of combination therapy describes genetically engineered CAR T cells with anti PD-1 activity. For instance, modified autologous T cells containing sequences encoding single-chain variable fragment unique to mesothelin and full-length antibody for PD-1, along with a small daily dose of aptinib, showed success in advanced refractory ovarian cancer (19). Similar studies have demonstrated success of cell extrinsic combination therapy, wherein the use of an anti-PD-1 agent can rescue function in depleted CAR T cells and strengthen antineoplastic efficacy, as demonstrated in a cohort of patients with malignant pleural mesothelioma (20). Both instances of combination therapy illustrate promising approaches, though future research is required.

Long-term risks

While acute toxicities of CAR T cell therapy, including CRS and immune effector cell-associated neurotoxicity syndrome (ICANS), are well described, the late and persistent complications in patients are less well understood. These include delayed neurotoxicity, prolonged cytopenias, late infections due to immune suppression, and secondary malignancies, particularly therapy-related myeloid neoplasms (21). Further research and long-term monitoring are needed to guide optimal care in this vulnerable population.

Conclusions

The application of CAR T cell therapy in treating prostate cancer is promising and has potential to become an important treatment option for CRPC, although future studies are needed to explore dosing for improved CAR T cell persistence and to identify strategies to mitigate toxicities. We eagerly anticipate continued progress in this field.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-25-44/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-44/coif). M.N.S. reports receiving consulting fees for a consulting or advisory role from Merck Sharp & Dohme, Exelixis, Xencor Research, Janssen Oncology, Vaccitech, Bristol-Myers Squibb/Medarex; and research funding from Bellicum Pharmaceuticals, Oncoceutics, Merck Sharp & Dohme, Janseen Oncology, Medivation/Astellas, Advaxis, Suzhou Kintor Pharmaceuticals, Harpoon, Bristol-Myers Squibb, Genocea Biosciences, Lilly, Nektar, Seattle Genetics, Tmunity, Exelixis, Regeneron, Bicycle Therapeutics, and AstraZeneca. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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