TY - JOUR
T1 - Immunotherapy targeting HPV16/18 generates potent immune responses in HPV-associated head and neck cancer
AU - Aggarwal, Charu
AU - Cohen, Roger B.
AU - Morrow, Matthew P.
AU - Kraynyak, Kimberly A.
AU - Sylvester, Albert J.
AU - Knoblock, Dawson M.
AU - Bauml, Joshua M.
AU - Weinstein, Gregory S.
AU - Lin, Alexander
AU - Boyer, Jean
AU - Sakata, Lindsay
AU - Tan, Sophie
AU - Anton, Aubrey
AU - Dickerson, Kelsie
AU - Mangrolia, Drishty
AU - Vang, Russell
AU - Dallas, Michael
AU - Oyola, Sandra
AU - Duff, Susan
AU - Esser, Mark
AU - Kumar, Rakesh
AU - Weiner, David
AU - Csiki, Ildiko
AU - Bagarazzi, Mark L.
N1 - Funding Information:
We would like to thank the patients who participated and their families as well as Hoyin Mok, Jiping Zha, and Lily Cheng for their work on the ACD and IHC data. We would also like to thank Histologix and OracleBio for assistance with additional IHC staining and digital image analysis. We would like to thank Alison Berry and Kristine Mykulowycz at the University of Pennsylvania for clinical research support. This study was supported by NCI P30 Cancer Center Support grant #5-P30-CA-016520-38.
Funding Information:
C. Aggarwal is a consultant/advisory board member for Bristol-Myers Squibb, Celgene, and Medimmune. R.B. Cohen reports receiving commercial research grants from and is a consultant/advisory board member for Innate. M.P. Morrow, K.A. Kraynak, A.J. Sylvester, D.M. Knoblock, M. Dallas, I. Csiki, and M. Bagarazzi hold ownership interest (including patents) in Inovio Pharmaceuticals. J. Bauml reports receiving commercial research grants from Astra Zeneca, Bayer, Incyte, Janssen, Merck, Novartis, and Takeda, and is a consultant/advisory board member for Astra Zeneca, Bristol-Myers Squibb,
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Purpose: Clinical responses with programmed death (PD-1) receptor–directed antibodies occur in about 20% of patients with advanced head and neck squamous cell cancer (HNSCCa). Viral neoantigens, such as the E6/E7 proteins of HPV16/18, are attractive targets for therapeutic immunization and offer an immune activation strategy that may be complementary to PD-1 inhibition. Patients and Methods: We report phase Ib/II safety, tolerability, and immunogenicity results of immunotherapy with MEDI0457 (DNA immunotherapy targeting HPV16/18 E6/E7 with IL12 encoding plasmids) delivered by electroporation with CELLECTRA constant current device. Twenty-two patients with locally advanced, p16þ HNSCCa received MEDI0457. Results: MEDI0457 was associated with mild injection site reactions, but no treatment-related grade 3–5 adverse events (AE) were noted. Eighteen of 21 evaluable patients showed elevated antigen-specific T-cell activity by IFNg ELISpot, and persistent cellular responses surpassing 100 spot-forming units (SFUs)/106 peripheral blood mononuclear cells (PBMCs) were noted out to 1 year. Induction of HPV-specific CD8þ T cells was observed. MEDI0457 shifted the CD8þ/FoxP3þ ratio in 4 of 5 post immunotherapy tumor samples and increased the number of perforinþ immune infiltrates in all 5 patients. One patient developed metastatic disease and was treated with anti–PD-1 therapy with a rapid and durable complete response. Flow-cytometric analyses revealed induction of HPV16-specific PD-1þ CD8þ T cells that were not found prior to MEDI0547 (0% vs. 1.8%). Conclusions: These data demonstrate that MEDI0457 can generate durable HPV16/18 antigen-specific peripheral and tumor immune responses. This approach may be used as a complementary strategy to PD-1/PD-L1 inhibition in HPV-associated HNSCCa to improve therapeutic outcomes.
AB - Purpose: Clinical responses with programmed death (PD-1) receptor–directed antibodies occur in about 20% of patients with advanced head and neck squamous cell cancer (HNSCCa). Viral neoantigens, such as the E6/E7 proteins of HPV16/18, are attractive targets for therapeutic immunization and offer an immune activation strategy that may be complementary to PD-1 inhibition. Patients and Methods: We report phase Ib/II safety, tolerability, and immunogenicity results of immunotherapy with MEDI0457 (DNA immunotherapy targeting HPV16/18 E6/E7 with IL12 encoding plasmids) delivered by electroporation with CELLECTRA constant current device. Twenty-two patients with locally advanced, p16þ HNSCCa received MEDI0457. Results: MEDI0457 was associated with mild injection site reactions, but no treatment-related grade 3–5 adverse events (AE) were noted. Eighteen of 21 evaluable patients showed elevated antigen-specific T-cell activity by IFNg ELISpot, and persistent cellular responses surpassing 100 spot-forming units (SFUs)/106 peripheral blood mononuclear cells (PBMCs) were noted out to 1 year. Induction of HPV-specific CD8þ T cells was observed. MEDI0457 shifted the CD8þ/FoxP3þ ratio in 4 of 5 post immunotherapy tumor samples and increased the number of perforinþ immune infiltrates in all 5 patients. One patient developed metastatic disease and was treated with anti–PD-1 therapy with a rapid and durable complete response. Flow-cytometric analyses revealed induction of HPV16-specific PD-1þ CD8þ T cells that were not found prior to MEDI0547 (0% vs. 1.8%). Conclusions: These data demonstrate that MEDI0457 can generate durable HPV16/18 antigen-specific peripheral and tumor immune responses. This approach may be used as a complementary strategy to PD-1/PD-L1 inhibition in HPV-associated HNSCCa to improve therapeutic outcomes.
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U2 - 10.1158/1078-0432.CCR-18-1763
DO - 10.1158/1078-0432.CCR-18-1763
M3 - Article
C2 - 30242022
AN - SCOPUS:85059479752
SN - 1078-0432
VL - 25
SP - 110
EP - 124
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 1
ER -