418 A phase 1, dose escalation and dose expansion study of SQZ PBMC HPV as monotherapy and in combination with atezolizumab in HLA-A*02+ Patients with HPV16+ recurrent, or metastatic solid tumors

BackgroundSQZ-PBMC-HPV is a therapeutic cancer vaccine created with Cell Squeeze®, a proprietary cell-engineering system. SQZ-PBMC-HPV is a novel cancer vaccine generated from peripheral blood mononuclear cells (PBMC) squeezed with HPV16 E6 and E7 antigens, resulting in delivery into the cytosol. The resulting antigen presenting cells (APCs) provide enhanced antigen presentation on MHC-I to potentially elicit robust, antigen-specific CD8+ T cell responses. Importantly, SQZ-PBMC-HPV are neither genetically modified nor immune effector cells.Studies in MHC-I knockout mice demonstrated that activation of antigen specific CD8+ tumor infiltrating lymphocytes (TILs) was a direct effect of cytosolic antigen delivery to PBMCs. In the murine TC-1 tumor model, tumor regression correlated with an influx of HPV16-specific CD8+ TILs. In vitro studies with human volunteer PBMCs demonstrated that each subset is capable of inducing CD8+ T cell responses. The Phase 1 study includes a significant biomarker program to investigate whether pharmacodynamic effects observed in non-clinical studies correlate with potential clinical benefit. Immunogenic and pharmacodynamic endpoints include Elispot assays to measure frequency of interferon gamma secreting cells, as well as quantification and characterization of TILs and tumor microenvironment. In addition, various cytokine responses and circulating cell-free HPV16 DNA levels in plasma are measured.MethodsSQZ-PBMC-HPV-101 (NCT04084951) is open for enrollment to HLA A*02+ patients with HPV16+ recurrent, locally advanced or metastatic solid tumors and includes escalation cohorts for monotherapy and in combination with atezolizumab. After initial demonstration of safety, the study assesses dose effect by testing different cell dose levels, the effect of prolonged antigen priming in Cycle 1 [APC administration on Day 1 only compared to Days 1 and 2 (double priming)] and the impact of treatment duration to identify the optimal dose regimen. The cycle length is 3 weeks, and patients will receive SQZ-PBMC-HPV for up to 1 year or until available autologous drug product is exhausted. Atezolizumab will be administered for up to 1 year. Eligible patients including but not limited to anal, cervical and head and neck tumors will undergo a single leukapheresis at the study site. The manufacturing process includes a maturation step and takes less than 24 hours. The vein-to-vein time for the 1st administration is approximately one week. Patients must have a lesion that can be biopsied with acceptable clinical risk and agree to have a fresh biopsy at Screening and on study. A Study Safety Committee is in place. No formal statistical hypothesis testing will be performed.ResultsN/AConclusionsN/ATrial RegistrationNCT04084951Ethics ApprovalThe study is registered on clinicaltrials.gov was approved by the Ethics Board of all institution listed as recruiting.

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CXCL14 suppresses human papillomavirus-associated head and neck cancer through antigen-specific CD8+ T-cell responses by upregulating MHC-I expression

Oncogene ◽

10.1038/s41388-019-0911-6 ◽

2019 ◽

Vol 38 (46) ◽

pp. 7166-7180 ◽

Cited By ~ 4

Author(s):

Joseph A. Westrich ◽

Daniel W. Vermeer ◽

Alexa Silva ◽

Stephanie Bonney ◽

Jennifer N. Berger ◽

...

Keyword(s):

Head And Neck Cancer ◽

Human Papillomavirus ◽

T Cell ◽

Head And Neck ◽

Neck Cancer ◽

T Cell Responses ◽

Cd8 T Cell ◽

Mhc I ◽

Cell Responses

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584 Powerful synergistic effects of a STING agonist and the IL-2 superkine, H9, in eliciting NK and T cell responses against MHC I- and MHC I+ tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.584 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A614-A614

Author(s):

Natalie Wolf ◽

Cristina Blaj ◽

Lora Picton ◽

Gail Snyder ◽

Li Zhang ◽

...

Keyword(s):

T Cell ◽

Combination Therapy ◽

Nk Cells ◽

Nk Cell ◽

Tumor Regression ◽

T Cell Responses ◽

Cd8 T Cell ◽

Mhc I ◽

Therapy Regimen ◽

Cell Responses

BackgroundMost current cancer immunotherapies are based on mobilizing CD8 T cell responses. However, many types of tumors evade CD8 T cell recognition by displaying few or no antigens, or losing expression of MHC I. These considerations underlie the need for complementary therapies that mobilize other antitumor effector cells, such as NK cells, which preferentially kill MHC I-deficient cells. Cyclic dinucleotides (CDNs) activate the cGAS-STING pathway of the innate immune system and are candidates as immunotherapy agents. Intratumoral CDN injections induce type I IFNs and other mediators that amplify the CD8 T cell response and induce tumor regression [1]. CDN therapy also induces long-term tumor regressions in some MHC I-deficient tumor models, mediated primarily by NK cells [2].MethodsTo extend the efficacy of CDN therapy, we combined the IL-2 superkine, H9, or half-life extended H9, with CDNs to target and activate NK cells in the tumor microenvironment and prevent or delay the onset of NK cell desensitization [3,4]. In these studies, we utilized B16-F10 and MC38 tumor cells lacking B2m to examine effects of the combination therapy on MHC I-deficient tumor growth as well as to examine the activation of NK cells by flow cytometry and cytotoxicity assays. We also utilized B16-F10 WT and the spontaneous tumor model, MCA, to assess the effect of the combination therapy on MHC I+ tumors.ResultsHere we show that H9 synergized with CDN therapy to mobilize much more powerful antitumor responses against MHC I-deficient tumors than CDN alone. The responses were mediated by NK cells and in some cases CD4 T cells, and were accompanied by increased recruitment to and sustained activation of NK cells in the tumor. This combination therapy regimen activated NK cells systemically, as shown by antitumor effects distant from the site of CDN injection and enhanced cytolytic activity of splenic NK cells against tumor cell targets ex vivo. Finally, the same combination therapy regimen synergistically mobilized powerful CD8 T cell responses in the case of MHC I+ tumor cells, suggesting the generality of the approach. The approach was effective against primary sarcomas, as well, especially when combined with checkpoint therapy, leading to tumor regressions and long-term survival of many mice with MCA-induced sarcoma.ConclusionsOverall, our work demonstrates the impact of a novel combination therapy in mobilizing powerful NK and T cell-mediated antitumor activity, providing important justification for evaluating this approach for treating cancers that are refractory to available treatment options.ReferencesCorrales, L., Glickman, L.H., McWhirter, S.M., Kanne, D.B., Sivick, K.E., Katibah, G.E., Woo, S.R., Lemmens, E., Banda, T., Leong, J.J., et al. (2015). Direct Activation of STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor Regression and Immunity. Cell Rep 11, 1018–1030.Nicolai, C.J., Wolf, N., Chang, I.C., Kirn, G., Marcus, A., Ndubaku, C.O., McWhirter, S.M., and Raulet, D.H. (2020). NK cells mediate clearance of CD8(+) T cell-resistant tumors in response to STING agonists. Science immunology 5, eaaz2738.Levin, A.M., Bates, D.L., Ring, A.M., Krieg, C., Lin, J.T., Su, L., Moraga, I., Raeber, M.E., Bowman, G.R., Novick, P., et al. (2012). Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine’. Nature 484, 529–533.Ardolino, M., Azimi, C.S., Iannello, A., Trevino, T.N., Horan, L., Zhang, L., Deng, W., Ring, A.M., Fischer, S., Garcia, K.C., and Raulet, D.H. (2014). Cytokine therapy reverses NK cell anergy in MHC-deficient tumors. J Clin Invest 124, 4781–4794.

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Novel Vβ specific germline contacts shape an elite controller T cell response

10.1101/2020.05.31.102566 ◽

2020 ◽

Cited By ~ 1

Author(s):

Yang Wang ◽

Alexandra Tsitsiklis ◽

Wei Gao ◽

H. Hamlet Chu ◽

Yan Zhang ◽

...

Keyword(s):

T Cell ◽

Cell Response ◽

T Cell Responses ◽

Cd8 T Cell ◽

Structural Features ◽

T Cell Response ◽

Elite Controller ◽

Unusual Structure ◽

Mhc I ◽

Cell Responses

AbstractCertain CD8 T cell responses are particularly effective at controlling infection, as exemplified by elite control of HIV in individuals harboring HLA-B57. To understand the structural features that contribute to CD8 T cell elite control, we focused on a strongly protective CD8 T cell response directed against a parasite-derived peptide (HF10) presented by an atypical MHC-I molecule, H-2Ld. This response exhibits a focused TCR repertoire dominated by Vβ2, and a representative TCR (TG6) in complex with Ld-HF10 reveals an unusual structure in which both MHC and TCR contribute extensively to peptide specificity, along with a parallel footprint of TCR on its pMHC ligand. The parallel footprint is a common feature of Vβ2-containing TCRs and correlates with an unusual Vα-Vβ interface, CDR loop conformations, and Vβ2-specific germline contacts with peptide. Vβ2 and Ld may represent “specialist” components for antigen recognition that allow for particularly strong and focused T cell responses.

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Therapy-Induced MHC I Ligands Shape Neo-Antitumor CD8 T Cell Responses during Oncolytic Virus-Based Cancer Immunotherapy

Journal of Proteome Research ◽

10.1021/acs.jproteome.9b00173 ◽

2019 ◽

Vol 18 (6) ◽

pp. 2666-2675 ◽

Cited By ~ 4

Author(s):

J. Patrick Murphy ◽

Youra Kim ◽

Derek R. Clements ◽

Prathyusha Konda ◽

Heiko Schuster ◽

...

Keyword(s):

T Cell ◽

Cancer Immunotherapy ◽

Oncolytic Virus ◽

T Cell Responses ◽

Cd8 T Cell ◽

Mhc I ◽

Cell Responses

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390 Emerging safety and activity data from GEN-009–101: A phase 1/2a trial of GEN-009, a neoantigen vaccine in combination with PD-1 check-point inhibitors (CPI) in advanced solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0390 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A415-A415

Author(s):

Maura Gillison ◽

Roger Cohen ◽

Przemyslaw Twardowski ◽

Ammar Sukari ◽

Melissa Johnson ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Antitumor Activity ◽

Immune Responses ◽

Solid Tumors ◽

Ex Vivo ◽

Phase 1 ◽

T Cell Responses ◽

Advanced Solid Tumors ◽

Cell Responses

BackgroundGEN-009 is an adjuvanted personalized cancer vaccine containing up to 20 neoantigens selected by ATLAS™, an ex vivo bioassay screening autologous T cells to identify both neoantigens as well as Inhibigens™ empirically and without in silico predictions. Inhibigen-specific T cells suppress immunity and have been shown to accelerate tumor progression in mice. Inhibigens are avoided in GEN-009. Previous data from patients treated with GEN-009 monotherapy showed 99% of selected peptides generated immune responses including ex vivo CD4+ and CD8+ fluorospot responses specific for 51% and 41% of immunized peptides respectively.MethodsGEN-009 is being evaluated in patients (pts) with advanced cancer who received standard-of-care (SOC) PD-1 inhibitor as monotherapy or in combination therapy during vaccine manufacturing; they subsequently received 5 vaccine doses over 24 weeks in combination with the PD-1 inhibitor. Patients who progressed prior to vaccination could receive alternate therapy followed by GEN-009 combined with an appropriate salvage regimen. Peripheral T cell responses were evaluated pre-and post-vaccination by dual-analyte fluorospot assays measured both directly ex vivo and after in vitro stimulation.ResultsAs of August 18, 2020, 15 pts received GEN-009 in combination with a PD-1 inhibitor. Their median TMB was 1.37Mut/mb (range 0.31–6.55), with a median of 24 (6–99) neoantigens and 16 (1–86) Inhibigens. The number of neoantigens in each manufactured vaccine ranged from 4–18 (median 13). GEN-009-related adverse events were limited to Grade 1 injection site reactions. Ex vivo T cell responses peaked after the third vaccination for IFNγ and some patients showed evidence of epitope spread. The initial 5 patients are evaluable for antitumor activity with at least 3 months follow up after first vaccination. Three patients experienced early tumor responses followed by stabilization on PD-1 inhibitor SOC and demonstrated a further reduction in tumor volume after GEN-009 vaccination (figure 1). One patient experienced a complete response prior to vaccination and the 5th patient had progression on SOC, but had a Partial Response to salvage and remains stable after vaccination.Abstract 390 Figure 1Individual patient spider plots. Percent change in target lesion diameter over timeConclusionsVaccination with GEN-009 in combination with PD-1 CPI is feasible for patients with advanced solid tumors with little additive toxicity. Preliminary data demonstrate induction of robust, neoantigen-specific immune responses and a potential expansion of stimulatory targets with epitope spreading in the presence of PD-1 inhibitor. Possible additive antitumor activity in combination with PD-1 inhibitors is suggested by tumor shrinkage following GEN-009 dosing. More mature response and immunogenicity data on 10 additional patients is anticipated for November.Trial RegistrationClinicalTrials. gov NCT03633110Ethics ApprovalThe study was approved by Western Institutional Review Board, approval number 1-1078861-1.

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589. Oral Tablet Vaccination Induces Heightened Cross-Reactive CD8 T Cell Responses to SARS-COV-2 in Humans

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.787 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S397-S397

Author(s):

Susan Johnson ◽

Clarissa Martinez ◽

Mario Cortese ◽

Josefina Martinez ◽

Shaily Garg ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Phase 1 ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Response ◽

Vaccine Platform ◽

Open Label ◽

Oral Tablet ◽

Cell Responses

Abstract Background Covid-19 has accelerated global demand for easily distributed vaccines. Furthermore, as variant SARS-CoV-2 strains that circumvent antibody responses emerge, cross-protective vaccines provide substantial public health benefits. Vaxart is developing a shelf stable oral tablet vaccine that incorporates both the spike (S) and the more conserved nucleocapsid (N) proteins. Vaxart’s vaccine platform uses a non-replicating adenovirus and a TLR3 agonist as an adjuvant. Methods In an open-label phase 1 clinical study, 35 healthy subjects received either a single low (1x1010 IU; n=15) or high (5x1010 IU; n=15) dose of the vaccine candidate VXA-CoV2-1 with a small cohort receiving 2 low doses. PBMCs were taken at pre- and 7 days post-vaccination and restimulated with S and N peptides from SARS-CoV-2 or the 4 human endemic coronaviruses (HCoV). Cells were stained for CD4/CD8/CD107a (surface) and IFNγ/TNFα (intracellular). Subjects that received an intramuscular (i.m.) mRNA vaccine had PBMCs taken at the same timepoints and were compared in the same assay. Results The study’s results indicate that the VXA-CoV2-1 tablet was well tolerated. The majority of subjects had an increase in S-specific anti-viral CD8+ T cell responses. 19/26 (73%) subjects had a measurable CD8+ T cell response on day 8 above baseline, on average 1.5-4.6%. In a comparator experiment with the 2 SARS-CoV-2 i.m. mRNA vaccines, VXA-CoV2-1 outperformed other vaccine candidates with a >3.5-fold increase in S specific antiviral CD8 T cell responses. T cell responses specific to the 4 endemic HCoV were increased by 0.6% in subjects given VXA-CoV2-1. Conclusion Here we describe a room temperature stable tablet that induces SARS-CoV-2 S specific CD8 T cells of high magnitude after one dose in humans. Overall, the level of antiviral SARS-CoV-2 specific T cells, particularly IFNg-producing CD8s, induced following oral immunization with VXA-CoV2-1 are of higher magnitude than the mRNA vaccines currently in use against COVID-19. T cell responses against 4 endemic HCoV were also induced. Because T cells may be important in protecting against death and severe infection, these results suggest that VXA-CoV2-1 could be cross-protective against a wide array of emerging pandemic coronaviruses. Disclosures Susan Johnson, PhD, Vaxart (Employee) Clarissa Martinez, MPH, Vaxart (Employee) Mario Cortese, PhD, Vaxart (Employee) Josefina Martinez, n/a, Vaxart (Employee) Shaily Garg, BS, Vaxart (Employee) Nadine Peinovich, MPH, Vaxart (Employee) Emery Dora, n/a, Vaxart (Employee) Sean Tucker, PhD, Vaxart (Employee)

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Targeting the Effector Site with IFN-αβ-Inducing TLR Ligands Reactivates Tumor-Resident CD8 T Cell Responses to Eradicate Established Solid Tumors

The Journal of Immunology ◽

10.4049/jimmunol.180.3.1535 ◽

2008 ◽

Vol 180 (3) ◽

pp. 1535-1544 ◽

Cited By ~ 50

Author(s):

Andrew J. Currie ◽

Robbert G. van der Most ◽

Steve A. Broomfield ◽

Amy C. Prosser ◽

Michael G. Tovey ◽

...

Keyword(s):

T Cell ◽

Solid Tumors ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Responses ◽

Effector Site

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Fibroblast-adapted human CMV vaccines elicit predominantly conventional CD8 T cell responses in humans

Journal of Experimental Medicine ◽

10.1084/jem.20161988 ◽

2017 ◽

Vol 214 (7) ◽

pp. 1889-1899 ◽

Cited By ~ 22

Author(s):

Susan E. Murray ◽

Pavlo A. Nesterenko ◽

Adam L. Vanarsdall ◽

Michael W. Munks ◽

Savannah M. Smart ◽

...

Keyword(s):

T Cell ◽

Human Subjects ◽

T Cell Responses ◽

Immune Deficiency Syndrome ◽

Cd8 T Cell ◽

Mhc I ◽

Virus Challenge ◽

Mhc Ii ◽

Cell Responses ◽

Human Cmv

Cytomegalovirus (CMV)-based vaccines have shown remarkable efficacy in the rhesus macaque model of acquired immune deficiency syndrome, enabling 50% of vaccinated monkeys to clear a subsequent virulent simian immunodeficiency virus challenge. The protective vaccine elicited unconventional CD8 T cell responses that were entirely restricted by MHC II or the nonclassical MHC I molecule, MHC-E. These unconventional responses were only elicited by a fibroblast-adapted rhesus CMV vector with limited tissue tropism; a repaired vector with normal tropism elicited conventional responses. Testing whether these unusual protective CD8 T responses could be elicited in humans requires vaccinating human subjects with a fibroblast-adapted mutant of human CMV (HCMV). In this study, we describe the CD8 T cell responses of human subjects vaccinated with two fibroblast-adapted HCMV vaccines. Most responses were identified as conventional classically MHC I restricted, and we found no evidence for MHC II or HLA-E restriction. These results indicate that fibroblast adaptation alone is unlikely to explain the unconventional responses observed in macaques.

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