IL-7 expands lymphocyte populations and enhances immune responses to sipuleucel-T in patients with metastatic castration-resistant prostate cancer (mCRPC)

Russell K. Pachynski, Chihiro Morishima, Russell Szmulewitz, Lauren Harshman, Leonard Appleman, Paul Monk, Rhonda L. Bitting, Omer Kucuk, Frederick Millard, John D. Seigne, Steven P. Fling, Holden T. Maecker, Caroline Duault, Nirasha Ramchurren, Bruce Hess, Leonard D'Amico, Andreanne Lacroix, Judith C. Kaiser, Michel Morre, Anne GrégoireMartin Cheever, Evan Y. Yu, Lawrence Fong

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4 Scopus citations

Abstract

Background Sipuleucel-T (sip-T) is a Food and Drug Administration (FDA)-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). We hypothesized that combining sip-T with interleukin (IL)-7, a homeostatic cytokine that enhances both B and T cell development and proliferation, would augment and prolong antigen-specific immune responses against both PA2024 (the immunogen for sip-T) and prostatic acid phosphatase (PAP). Methods Fifty-four patients with mCRPC treated with sip-T were subsequently enrolled and randomized 1:1 into observation (n=26) or IL-7 (n=28) arms of a phase II clinical trial (NCT01881867). Recombinant human (rh) IL-7 (CYT107) was given weekly×4. Immune responses were evaluated using flow cytometry, mass cytometry (CyTOF), interferon (IFN)-γELISpot, 3 H-thymidine incorporation, and ELISA. Results Treatment with rhIL-7 was well tolerated. For the rhIL-7-treated, but not observation group, statistically significant lymphocyte subset expansion was found, with 2.3-2.6-fold increases in CD4+T, CD8+T, and CD56 bright NK cells at week 6 compared with baseline. No significant differences in PA2024 or PAP-specific T cell responses measured by IFN-γELISpot assay were found between rhIL-7 and observation groups. However, antigen-specific T cell proliferative responses and humoral IgG and IgG/IgM responses significantly increased over time in the rhIL-7-treated group only. CyTOF analyses revealed pleiotropic effects of rhIL-7 on lymphocyte subsets, including increases in CD137 and intracellular IL-2 and IFN-γexpression. While not powered to detect clinical outcomes, we found that 31% of patients in the rhIL-7 group had prostate specific antigen (PSA) doubling times of >6 months, compared with 14% in the observation group. Conclusions Treatment with rhIL-7 led to a significant expansion of CD4+ and CD8+ T cells, and CD56 bright natural killer (NK) cells compared with observation after treatment with sip-T. The rhIL-7 treatment also led to improved antigen-specific humoral and T cell proliferative responses over time as well as to increased expression of activation markers and beneficial cytokines. This is the first study to evaluate the use of rhIL-7 after sip-T in patients with mCRPC and demonstrates encouraging results for combination approaches to augment beneficial immune responses.

Original languageEnglish
Article numbere002903
JournalJournal for ImmunoTherapy of Cancer
Volume9
Issue number8
DOIs
StatePublished - Aug 27 2021

Keywords

  • T-lymphocytes
  • clinical trials as topic
  • cytokines
  • immunotherapy
  • prostatic neoplasms

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