TY - JOUR
T1 - IL-7 expands lymphocyte populations and enhances immune responses to sipuleucel-T in patients with metastatic castration-resistant prostate cancer (mCRPC)
AU - Pachynski, Russell K.
AU - Morishima, Chihiro
AU - Szmulewitz, Russell
AU - Harshman, Lauren
AU - Appleman, Leonard
AU - Monk, Paul
AU - Bitting, Rhonda L.
AU - Kucuk, Omer
AU - Millard, Frederick
AU - Seigne, John D.
AU - Fling, Steven P.
AU - Maecker, Holden T.
AU - Duault, Caroline
AU - Ramchurren, Nirasha
AU - Hess, Bruce
AU - D'Amico, Leonard
AU - Lacroix, Andreanne
AU - Kaiser, Judith C.
AU - Morre, Michel
AU - Grégoire, Anne
AU - Cheever, Martin
AU - Yu, Evan Y.
AU - Fong, Lawrence
N1 - Funding Information:
and Judith C Kaiser @Fluffone Acknowledgements We are deeply indebted to the patients and their families and to staff at all clinical sites for their participation in and support of this study. This work was supported by grants from the National Cancer Institute: U01CA154967 and UM1CA154967 (to MC and SPF), Cancer Center Support Grant P30 CA015704 (to MC), and by Dendreon (Seattle, Washington, USA). In addition, support was provided by RevImmune (Paris, France). HTM and CD are supported by grant 1U24CA224309 from the NIH. LH is currently an employee of Surface Oncology, Cambridge, Massachusetts, USA. Contributors RKP: investigation, data analysis, writing—original draft, review and editing. CM: investigation, methodology, data analysis, writing—original draft, review and editing. RS: investigation, writing—original draft, review and editing. LH: investigation, writing—review and editing. LA: investigation, writing—review and editing. PM: investigation, writing—review and editing. RLB: investigation, writing—review and editing. OK: investigation, writing—review and editing. FM: investigation, writing—review and editing. JDS: investigation, writing—review and editing. SPF: investigation, methodology, data analysis, writing—original draft, review and editing, supervision, project administration, funding acquisition. HTM: investigation, data analysis, writing—original draft, review and editing. CD: investigation, data analysis, writing—original draft, review and editing. NR: investigation, data analysis, writing—review and editing. BH: investigation, data analysis, writing—review and editing. LD: investigation, data analysis, writing—review and editing. AL: project administration, supervision, data curation, writing—review and editing. JCK: project administration, supervision, data curation, writing—review and editing. MM: supervision, funding acquisition, writing—review and editing. AG: supervision, funding acquisition, writing—review and editing. MC: conceptualization, methodology, data analysis, writing—review and editing, supervision, project administration, funding acquisition. EYY: conceptualization, investigation, methodology, writing—review and editing. LF: conceptualization, investigation, methodology, data analysis, writing—original draft, review and editing, supervision, project administration, funding acquisition.
Funding Information:
Funding This work was supported by grants from the National Cancer Institute and additional funding from Dendreon (Seattle, Washington) and support from RevImmune (Paris, France).
Publisher Copyright:
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2021/8/27
Y1 - 2021/8/27
N2 - 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.
AB - 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.
KW - T-lymphocytes
KW - clinical trials as topic
KW - cytokines
KW - immunotherapy
KW - prostatic neoplasms
UR - http://www.scopus.com/inward/record.url?scp=85114242607&partnerID=8YFLogxK
U2 - 10.1136/jitc-2021-002903
DO - 10.1136/jitc-2021-002903
M3 - Article
C2 - 34452927
AN - SCOPUS:85114242607
SN - 2051-1426
VL - 9
JO - Journal for ImmunoTherapy of Cancer
JF - Journal for ImmunoTherapy of Cancer
IS - 8
M1 - e002903
ER -