Kang and Han et al. developed PROTEXI, a vaccine platform comprising autologous DCs loaded with both tumor-specific CD8+ T and SARS-CoV-2 Spike protein CD4+ TH cell epitopes. In mouse tumor models, PROTEXI required both CD4+ and CD8+ T cells for efficacy and immune memory induction, and in ICI-resistant models, synergized with anti-PD-1 by revitalizing TEX cells. PROTEXI plus Vactosertib, a TGFβR inhibitor, activated “cold” TIMEs by driving T cell recruitment, cytotoxicity, and epitope spreading. PROTEXI was also efficacious in humanized mouse tumor models, dependent on pre-existing human CD4+ T cells against SARS-CoV-2 Spike epitopes.
Contributed by Paula Hochman
(1) Kang JM (2) Han EH (3) Choi JK (4) Youm S (5) Pareek T (6) Levi L (7) Kim SJ (8) Letterio J (9) Lim S
Kang and Han et al. developed PROTEXI, a vaccine platform comprising autologous DCs loaded with both tumor-specific CD8+ T and SARS-CoV-2 Spike protein CD4+ TH cell epitopes. In mouse tumor models, PROTEXI required both CD4+ and CD8+ T cells for efficacy and immune memory induction, and in ICI-resistant models, synergized with anti-PD-1 by revitalizing TEX cells. PROTEXI plus Vactosertib, a TGFβR inhibitor, activated “cold” TIMEs by driving T cell recruitment, cytotoxicity, and epitope spreading. PROTEXI was also efficacious in humanized mouse tumor models, dependent on pre-existing human CD4+ T cells against SARS-CoV-2 Spike epitopes.
Contributed by Paula Hochman
ABSTRACT: The efficacy of dendritic cell (DC) cancer vaccines is linked to poor immunogenicity of tumor-associated antigens and failure to elicit robust MHC class II-restricted CD4⁺ T-cell responses. Here, we introduce PROTEXI, a DC vaccine platform that optimizes tumor immunity by co-presenting tumor-specific CD8⁺ T-cell epitopes alongside CD4⁺ T helper epitopes from the SARS-CoV-2 Spike protein, leveraging widespread anti-viral immunity. In preclinical mouse models of melanoma and breast cancer, PROTEXI significantly reduces tumor growth and improves survival by promoting robust T cell infiltration into immune-cold tumors, increasing cytotoxic T cell responses via epitope spreading, and activating genes linked to optimal DC, NK cell, and T cell function. Furthermore, PROTEXI elicits superior responses when combined with other immunotherapy agents in models of therapy-resistant tumors. Finally, in a humanized mouse model of melanoma, PROTEXI vaccine co-presenting CD4⁺ T-specific Spike epitopes with CD8⁺ T cell-restricted PRAME and MAGE-A3 antigens, significantly reduces tumor burden. Thus, these data underscore the potential of harnessing pre-existing viral-specific immunity to enhance the efficacy of DC vaccines in immune-cold tumors.
Author Info:
(1) The Angie Fowler Adolescent & Young Adult Cancer Institute, University Hospitals Rainbow Babies & Children's Hospital, Cleveland, OH, USA. Department of Pediatric Hematology &
Oncology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA. (2) Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA. (3) Celloram Inc., 11000 Cedar Avenue STE 100F #23, Cleveland, OH, USA. (4) Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA. (5) Celloram Inc., 11000 Cedar Avenue STE 100F #23, Cleveland, OH, USA. (6) Celloram Inc., 11000 Cedar Avenue STE 100F #23, Cleveland, OH, USA. (7) MedPacto Inc., 92, Myeongdal-ro, Seocho-gu, Seoul, Republic of Korea. (8) The Angie Fowler Adolescent & Young Adult Cancer Institute, University Hospitals Rainbow Babies & Children's Hospital, Cleveland, OH, USA. John.Letterio@UHHospitals.org. Department of Pediatric Hematology & Oncology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA. John.Letterio@UHHospitals.org. Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA. John.Letterio@UHHospitals.org. The Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA. John.Letterio@UHHospitals.org. (9) The Angie Fowler Adolescent & Young Adult Cancer Institute, University Hospitals Rainbow Babies & Children's Hospital, Cleveland, OH, USA. SeunghwanLim@Celloram.com. Celloram Inc., 11000 Cedar Avenue STE 100F #23, Cleveland, OH, USA. SeunghwanLim@Celloram.com.
