Dataset Information

Phase II Trial of Pembrolizumab and Anti-CD3 x Anti-HER2 Bispecific Antibody-Armed Activated T Cells in Metastatic Castration-Resistant Prostate Cancer.

ABSTRACT:

Purpose

A phase II study was conducted to evaluate the safety and efficacy of the combination of HER2 bispecific antibody (HER2Bi)-armed activated T cells (HER2 BAT) and programmed death 1 inhibitor, pembrolizumab.

Patients and methods

Patients with metastatic castration-resistant prostate cancer (mCRPC) with 0 to 1 performance status and normal liver, kidney, and marrow function, pre- or post-docetaxel chemotherapy were eligible. Primary endpoint was 6-month progression-free survival (PFS). Peripheral blood mononuclear cells were obtained by a single apheresis, shipped to University of Virginia, activated with OKT3 and expanded for 14 days in IL2, harvested, and armed with HER2Bi and cryopreserved. HER2 BATs were infused twice weekly for 4 weeks and pembrolizumab was administered every 21 days for a maximum duration of 6 months starting 1 to 3 weeks prior to HER2 BATs infusion.

Results

Fourteen patients were enrolled with a median age of 69 (range 57-82 years) and median PSA of 143.4 (range 8.2-4210 ng/dL). Two patients had peritoneal metastases, 1 had lymph node (LN) only metastases and 11 had bone metastases of which 7 had bone and LN metastases. All were pretreated with androgen receptor axis targeted agents and 7 (50%) had prior docetaxel chemotherapy. The toxicities were grade1-2 infusion reactions with fever, chills, headaches, nausea and/or myalgias. Primary endpoint of 6 month PFS was achieved in 5 of 14 patients (38.5%; 95% confidence interval, 19.5%-76.5%). Median PFS was 5 months and median survival was 31.6 months.

Conclusions

The safety and promising efficacy makes this combination worthy of future investigation in mCRPC.

SUBMITTER: Vaishampayan UN

PROVIDER: S-EPMC9812860 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

Phase II Trial of Pembrolizumab and Anti-CD3 x Anti-HER2 Bispecific Antibody-Armed Activated T Cells in Metastatic Castration-Resistant Prostate Cancer.

Vaishampayan Ulka N UN Thakur Archana A Chen Wei W Deol Abhinav A Patel Meera M Dobson Kimberlee K Dickow Brenda B Schalk Dana D Schienschang Amy A Whitaker Sarah S Polend Amanda A Fontana Joseph A JA Heath Elisabeth I EI Lum Lawrence G LG

Clinical cancer research : an official journal of the American Association for Cancer Research 20230101 1

<h4>Purpose</h4>A phase II study was conducted to evaluate the safety and efficacy of the combination of HER2 bispecific antibody (HER2Bi)-armed activated T cells (HER2 BAT) and programmed death 1 inhibitor, pembrolizumab.<h4>Patients and methods</h4>Patients with metastatic castration-resistant prostate cancer (mCRPC) with 0 to 1 performance status and normal liver, kidney, and marrow function, pre- or post-docetaxel chemotherapy were eligible. Primary endpoint was 6-month progression-free surv ...[more]

PMID: 36255393

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Project description:BackgroundThe survival benefit observed in children with neuroblastoma (NB) and minimal residual disease who received treatment with anti-GD2 monoclonal antibodies prompted our investigation into the safety and potential clinical benefits of anti-CD3×anti-GD2 bispecific antibody (GD2Bi) armed T cells (GD2BATs). Preclinical studies demonstrated the high cytotoxicity of GD2BATs against GD2+cell lines, leading to the initiation of a phase I/II study in recurrent/refractory patients.MethodsThe 3+3 dose escalation phase I study (NCT02173093) encompassed nine evaluable patients with NB (n=5), osteosarcoma (n=3), and desmoplastic small round cell tumors (n=1). Patients received twice-weekly infusions of GD2BATs at 40, 80, or 160×106 GD2BATs/kg/infusion complemented by daily interleukin-2 (300,000 IU/m2) and twice-weekly granulocyte macrophage colony-stimulating factor (250 µg/m2). The phase II segment focused on patients with NB at the dose 3 level of 160×106 GD2BATs/kg/infusion.ResultsOf the 12 patients enrolled, 9 completed therapy in phase I with no dose-limiting toxicities. Mild and manageable cytokine release syndrome occurred in all patients, presenting as grade 2-3 fevers/chills, headaches, and occasional hypotension up to 72 hours after GD2BAT infusions. GD2-antibody-associated pain was minimal. Median overall survival (OS) for phase I and the limited phase II was 18.0 and 31.2 months, respectively, with a combined OS of 21.1 months. A phase I NB patient had a complete bone marrow response with overall stable disease. In phase II, 10 of 12 patients were evaluable: 1 achieved partial response, and 3 showed clinical benefit with prolonged stable disease. Over 50% of evaluable patients exhibited augmented immune responses to GD2+targets post-GD2BATs, as indicated by interferon-gamma (IFN-γ) EliSpots, Th1 cytokines, and/or chemokines.ConclusionsThis study demonstrated the safety of GD2BATs up to 160×106 cells/kg/infusion. Coupled with evidence of post-treatment endogenous immune responses, our findings support further investigation of GD2BATs in larger phase II clinical trials.

Project description:BackgroundSince treatment of neuroblastoma (NB) with anti-GD2 monoclonal antibodies provides a survival benefit in children with minimal residual disease and our preclinical study shows that anti-CD3 x anti-GD2 bispecific antibody (GD2Bi) armed T cells (GD2BATs) were highly cytotoxic to GD2+ cell lines, we conducted a phase I/II study in recurrent/refractory patients to establish safety and explore the clinical benefit of GD2BATs.MethodsThe 3+3 dose escalation study (NCT02173093) phase I involved 9 evaluable patients with NB (n=5), osteosarcoma (OST) (n=3), and desmoplastic small round cell tumors (DSRCT) (n=1) with twice weekly infusions of GD2BATs at 40, 80, or 160 x 106 GD2BATs/kg/infusion with daily interleukin 2 (300,000 IU/m2) and twice weekly granulocyte-macrophage colony stimulating factor (250 μg/m2). Phase II portion of the trial was conducted in patients with NB at the dose 3 level of 160 x 106 GD2BATs/kg/infusion but failed to enroll the planned number of patients.ResultsNine of 12 patients in the phase I completed therapy. There were no dose limiting toxicities (DLTs). All patients developed mild and manageable cytokine release syndrome (CRS) with grade 2-3 fevers/chills, headaches, and occasional hypotension up to 72 hours after GD2BAT infusions. GD2-antibody associated pain was not significant in this study. The median OS for patients in the Phase I and limited Phase II was 18.0 and 31.2 months, respectively, whereas the combined OS was 21.1 months. There was a complete bone marrow response with overall stable disease in one of the phase I patients with NB. Ten of 12 phase II patients were evaluable for response: 1 had partial response. Three additional patients were deemed to have clinical benefit with prolonged stable disease. More than 50% of evaluable patients showed augmented immune responses to GD2+ targets after GD2BATs as measured by interferon-gamma (IFN-γ) EliSpots, Th1 cytokines, and/or chemokines.ConclusionsOur study demonstrated safety of up to 160 x 106 cells/kg/infusion of GD2BATs. Combined with evidence for the development of post treatment endogenous immune responses, this data supports further investigation of GD2 BATs in larger Phase II clinical trials.

Dataset Information

Phase II Trial of Pembrolizumab and Anti-CD3 x Anti-HER2 Bispecific Antibody-Armed Activated T Cells in Metastatic Castration-Resistant Prostate Cancer.

Purpose

Patients and methods

Results

Conclusions

Publications

Phase II Trial of Pembrolizumab and Anti-CD3 x Anti-HER2 Bispecific Antibody-Armed Activated T Cells in Metastatic Castration-Resistant Prostate Cancer.

Similar Datasets

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