(UroToday.com) At the 2020 European Society for Medical Oncology Virtual Congress (ESMO), Dr. Ben Tran presented AMG 160, a half-life extended, PSMA-targeted, bispecific T-cell engager (BiTE®) for patients with metastatic castration-resistant prostate cancer (mCRPC) (NCT03792841). Dr. Cora Sternberg then provided the invited discussant presentation of this novel research in prostate immunotherapy.
To date, immunotherapy with checkpoint inhibitors and vaccines have offered limited efficacy in mCRPC, including targeting of CTLA-4 with ipilimumab, G-VAX, Prostvac, and pembrolizumab after enzalutamide. However, the recent emergence of BiTEs, T-cell engagers, CAR-T cells, and antibody-drug conjugates have provided renewed hope for immunotherapy in this disease space. Dr. Sternberg notes that there has been some success with immunotherapy in prostate cancer, notably:
- Sipuleucel-T (IMPACT phase III trial): median OS of sipuleucel-T of 25.8 months vs median OS of placebo of 21.7 months (HR 0.78, 95% CI 0.61-0.98).1
- Ipilimumab following radiotherapy (CA184-043 phase III trial): median OS of ipilimumab of 11.0 months vs median OS of placebo of 10.0 months (piecewise HR 0-5 months of 1.49, 95% CI 1.12-1.99; piecewise HR 5-12 months of 0.66, 95% CI 0.51-0.86; piecewise HR >12 months of 0.66, 95% CI 0.52-0.84).2
Regarding immunotherapy and PSMA for mCRPC, cytotoxic T cells play an important role in the body’s immune defense against cancer, as cancer cells can develop mechanisms to evade T-cell recognition and destruction. Indeed, redirection of T-cells against tumors holds promise for the treatment of many cancers, however many immuno-oncology therapies and chemotherapies do not target tumor-associated antigens. Additionally, there is a dire need for novel therapies in mCRPC, and unlike PSA, PSMA has the potential to serve both as a radiodiagnostic marker and as a target for new therapies.
There are two main approaches for T-cell redirection involving their genetic modification: (i) T-cell engagers (BiTE® and others), and (ii) chimeric antigen receptors (CAR-T). Thus far, there has been dramatic effects in patients with hematologic malignancies for CAR-T therapy, but limited effect against solid cancers. In solid tumors, the antigens are not limited to their tissue of origin, and we must address the safety concerns related to “on-target” and “off-target” activity in healthy tissue. Furthermore, there is a need to manipulate the tumor micro-environment from a “cold” tumor to a “hot” one. As follows is a schematic for the design of BiTE®, and for the specific configuration of the BiTE® for PSMA:
Once T-cells are activated by the BiTE® molecule, the T-cells induce T-cell proliferation and cytokine production. With cancer cell apoptosis, activated T-cells release cytokines and produce perforin and granzymes that allows T-cells to target surrounding cancer cells, which potentially results in serial lysis of multiple cancer cells by a single T-cell. Furthermore, sustained activation of a single activated cytotoxic T-cell results in local proliferation and expansion of polyclonal memory cells. As follows is a summary of the differences between chimeric antigen receptors, and bispecific T-cell engagers, specifically highlighting their structure, effector cell types, immune synapse, serial killing, killing mechanism, trafficking, toxicity, and clinical applications:
Dr. Sternberg notes that there are several ongoing T-cell engager clinical trials in prostate cancer:
- AMG 160, bispecific half-life extended PSMA-targeted T-cell engager (BiTE®) +/- pembrolizumab anti-PD-1 (NCT03792841)
- HPN424, trispecific half-life extended PSMA-targeted T-cell engager (NCT03577028)
- REGN5678, bispecific PSMA-targeted T-cell engager +/- cemiplimab anti-PD-1 (NCT03972657)
- JNJ-63898081, bispecific monoclonal antibody against PSMA (NCT03926013)
Similarly, there are several ongoing CAR-T clinical trials in prostate cancer:
- P-PSMA-101 +/- rimiducid (NCT04249947)
- PSMA-specific CAR-T (NCT04053062)
- Dual PSMA-specific/TGFB-resistant CAR-T (NCT03089203)
- Anti-PSCA-CAR-41BB/TCRzeta-CD19t expressing CAR-T (NCT03873805)
- BPX-601 antiPSCA CAR-T + rimiducid (NCT02744287)
- Anti-EpCAM-CAR-CD3zeta-CD28 (NCT03013712)
For the AMG 160 trial, 43 patients had received ≥ 1 dose of AMG 160 monotherapy at 6 dose levels, and 19 patients (44.2%) were still on treatment (6 for ≥ 6 months). Among these patients, 41 (95.3%) experienced a treatment-related adverse event, most commonly cytokine release syndrome (n=30, 90.7% all grade; n=11, 25.6% grade 3). Cytokine release syndrome was reversible, manageable, and most severe in cycle 1, with associated fever, hypotension, transient transaminitis, nausea/vomiting, and/or diarrhea. There were 26 patients (60.5%) that had grade 2 cytokine release syndrome as the worst grade, and 11 patients (25.6%) that had grade 3 cytokine release syndrome as the worst grade; 4 patients (9.3%) experienced reversible atrial fibrillation in the setting of cytokine release syndrome/tachycardia. There were no grade 5 events and none of the treatment-related adverse events resulted in treatment discontinuation. There was a confirmed PSA response in 27.6% of patients, an unconfirmed PSA response in 11.4% of patients, and a CTC0 response in 23.1% of patients. Among patients with RECIST measurable disease, 13.3% had confirmed partial response, 6.7% had an unconfirmed partial response, and 53.3% had stable disease. PSA reductions (best response) were dose-dependent and occurred in 24/35 (68.6%) of evaluable patients at the data cutoff of July 20, 2020, whereas PSA reductions >50% occurred in 12/35 (34/3%) of evaluable patients.
Dr. Sternberg noted the following advantages of the novel BiTE® technology:
- This is off the shelf technology, with no problems with histocompatibility, no need for preparative chemotherapy, and no need for leukapheresis
- Responses are durable (some ~300 days) and stable disease is important in these heavily pretreated patients
- There is a reasonable toxicity profile with a prophylactic mitigation strategy against cytokine release syndrome, and toxicity equal to or less than antibody-drug conjugates and perhaps CAR-T cells
- Half-life extended technology allows administration every two weeks and the continuous infusion is not required
Amid the encouraging results, Dr. Sternberg notes several remaining questions, including (i) Does it only work for PSMA positive patients, and what is the specificity for PSMA? (ii) What is the effect if 20% developed anti-drug antibodies affecting exposure? (iii) Prophylactic steroids are needed against cytokine release syndrome; (iv) There is no information yet on the combination with pembrolizumab, and the toxicity may be more; (v) It would have been nice to see FDG vs PSMA PET responses side by side; (vi) Is there a change in biology over time? (vii) Are there changes in cytokines? (viii) What are the genomic alterations in the responders and non-responders? (ix) Who are the patients that had a complete response and what is there biology? Biopsies of these patients would have been interesting; (x) Will the combination with checkpoint inhibitors or stroma disruptors produce better responses? (xi) Can this therapy eventually be given in the community or only in academic centers? (xii) The question of durability remains to be answered.
1. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010;363(5):411-422.
2. Fizazi K, Drake CG, Beer TM, et al. Final analysis of the ipilimumab versus placebo following radiotherapy phase III trial in post docetaxel metastatic castration-resistant prostate cancer identifies an excess of long-term survivors. Eur Urol. 2020 Aug 15; S0302-2838(20)30604-7.
Presented by: Cora N. Sternberg, MD, Weill Cornell Medicine, New York, NY
Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md, at the 2020 European Society for Medical Oncology Virtual Congress (#ESMO20), September 19th-September 21st, 2020.
ESMO Virtual Congress 2020: Results from a Phase 1 Study of AMG 160, a Half-Life Extended, PSMA-Targeted, Bispecific T-Cell Engager (BiTE®) Immune Therapy for Metastatic Castration-Resistant Prostate Cancer
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