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Phase I trial of antigen-targeted autologous dendritic cell-based vaccine with in vivo activation of inducible CD40 for advanced prostate cancer

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Abstract

This phase I trial reports the safety and activity of BPX101, a second-generation antigen-targeted autologous antigen presenting cell (APC) vaccine in men with metastatic castration-resistant prostate cancer (mCRPC). To manufacture BPX101, APCs collected in a single leukapheresis were transduced with adenoviral vector Ad5f35 encoding inducible human (ih)-CD40, followed by incubation with protein PA001, which contains the extracellular domain of human prostate-specific membrane antigen. The ih-CD40 represents a modified chimeric version of the dendritic cell (DC) co-stimulatory molecule, CD40, which responds to a bioinert membrane-permeable activating dimerizer drug, rimiducid (AP1903), permitting temporally controlled, lymphoid-localized, DC-specific activation. Eighteen men with progressive mCRPC following ≤1 prior chemotherapy regimen were enrolled to evaluate three doses of BPX101 (4 × 106, 12.5 × 106 and 25 × 106 cells) administered intradermally every 2–4 weeks followed by rimiducid (0.4 mg/kg) intravenous (IV) infusion 24 h after each BPX101 dose. There were no dose-limiting toxicities. Immune upregulation as well as anti-tumor activity was observed with PSA declines, objective tumor regressions and robust efficacy of post-trial therapy. This novel antigen-targeted and in vivo activated immunotherapy platform may warrant further development as monotherapy and as a component of rational combinations.

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Abbreviations

AE:

Adverse event

CT:

Computerized tomography

CTC:

Circulating tumor cell

CTCAE:

Common Toxicity Criteria for Adverse Events

DLTs:

Dose-limiting toxicities

FKBP:

FK506-binding protein

HbsAg:

Hepatitis B surface antigen

HTLV:

Human T-cell lymphotropic virus

ih:

Inducible human

IHC:

Immunohistochemistry

KPS:

Karnofsky Performance Score

LPS:

Lipopolysaccharide

MCP:

Monocyte chemoattractant protein

mCRPC:

Metastatic castration-resistant prostate cancer

MTD:

Maximum tolerated dose

PAP:

Prostatic-acid phosphatase

PCWG:

Prostate Cancer Working Group

PFS:

Progression-free survival

PR:

Partial response

PSA:

Prostate-specific antigen

PSMA:

Prostate-specific membrane antigen

RANTES:

Regulated on activation, normal T cell expressed and secreted

RECIST:

Response Evaluation Criteria in Solid Tumors

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Acknowledgements

We thank the Clinical Research Unit and Center for Clinical and Translational Sciences University of Texas Health Science Center at Houston for supporting the conduct of this trial.

Author information

Authors and Affiliations

  1. University of Alabama at Birmingham (UAB) Comprehensive Cancer Center, 1720 2nd Ave. S., NP2540B, Birmingham, AL, USA

    Guru Sonpavde

  2. The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    John D. McMannis

  3. Mesoblast Ltd, Houston, TX, 35294, USA

    John D. McMannis

  4. The University of Texas Health Science Center Houston, Houston, TX, USA

    Yu Bai, Joan M. C. Bull, Victoria Hawkins & Theresa K. Dancsak

  5. Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, USA

    Mamatha R. Seethammagari, Natasha Lapteva & Jonathan M. Levitt

  6. Bellicum Pharmaceuticals Inc., Houston, TX, USA

    Annemarie Moseley, David M. Spencer & Kevin M. Slawin

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  1. Guru Sonpavde
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Corresponding author

Correspondence to Guru Sonpavde.

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Conflict of interest

G. Sonpavde: Consultant for Bayer, Sanofi, Pfizer, Novartis, Eisai, Janssen, Amgen, Astrazeneca, Merck, Genentech, Argos, Agensys; research support to institution from Bellicum, Bayer, Onyx, Celgene, Boehringer-Ingelheim, Merck, Pfizer; author for Uptodate; speaker for Clinical Care Options. J.D. McMannis, Y. Bai, M. Seethammagari, J.M.C. Bull, V. Hawkins, T. Dancsak, N. Lapteva, J.M. Levitt: funding to institution by Bellicum Pharmaceuticals, Inc. D.M. Spencer, A. Moseley, K.M. Slawin: employed by and shareholders of Bellicum Pharmaceuticals, Inc.

Research involving human participants

The protocol was approved by the institutional review boards (IRBs) at the University of Texas, Houston, Texas.

Informed consent

All participants provided written informed consent. The trial was registered at ClinicalTrials.gov under the identification NCT00868595.

Financial support

The trial was funded and sponsored by Bellicum Pharmaceuticals, Inc.

Additional information

Previous presentations:

Poster presentations at the ASCO (American Society of Clinical Oncology) annual conference, Chicago, IL, USA in June 2011 (J Clin Oncol 2011; 29: abstract 4670; J Clin Oncol 2011; 29: abstract 167).

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Sonpavde, G., McMannis, J.D., Bai, Y. et al. Phase I trial of antigen-targeted autologous dendritic cell-based vaccine with in vivo activation of inducible CD40 for advanced prostate cancer. Cancer Immunol Immunother 66, 1345–1357 (2017). https://doi.org/10.1007/s00262-017-2027-6

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  • DOI: https://doi.org/10.1007/s00262-017-2027-6

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