Adaptive immunity to SARS-CoV-2 in cancer patients: The CAPTURE study

SUMMARYThere is a pressing need to characterise the nature, extent and duration of immune response to SARS-CoV-2 in cancer patients and inform risk-reduction strategies and preserve cancer outcomes. CAPTURE is a prospective, longitudinal cohort study of cancer patients and healthcare workers (HCWs) integrating longitudinal immune profiling and clinical annotation. We evaluated 529 blood samples and 1051 oronasopharyngeal swabs from 144 cancer patients and 73 HCWs and correlated with >200 clinical variables. In patients with solid cancers and HCWs, S1-reactive and neutralising antibodies to SARS-CoV-2 were detectable five months post-infection. SARS-CoV-2-specific T-cell responses were detected, and CD4+ T-cell responses correlated with S1 antibody levels. Patients with haematological malignancies had impaired but partially compensated immune responses. Overall, cancer stage, disease status, and therapies did not correlate with immune responses. These findings have implications for understanding individual risks and potential effectiveness of SARS-CoV-2 vaccination in the cancer population.

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T Cell Responses in Patients Vaccinated with Telomerase (hTERT)-mRNA Transfected Dendritic Cells.

Blood ◽

10.1182/blood.v114.22.373.373 ◽

2009 ◽

Vol 114 (22) ◽

pp. 373-373

Author(s):

Else Marit Inderberg Suso ◽

Anne-Marie Rasmussen ◽

Steinar Aamdal ◽

Svein Dueland ◽

Gustav Gaudernack ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Immune Responses ◽

Cancer Patients ◽

Cd8 T Cells ◽

Stable Disease ◽

T Cell Responses ◽

Htert Mrna ◽

Cell Responses

Abstract Abstract 373 Two cancer patients were vaccinated with dendritic cells (DC) loaded with telomerase (hTERT) mRNA to investigate the safety, tolerability and immunological response to vaccination prior to the start of a new phase I/II clinical trial. Following written informed consent one primary lung adenocarcinoma with metastasis and one patient with a relapsed pancreatic ductal type of adenocarcinoma, were treated with autologus monocyte-derived DC transfected with mRNA encoding hTERT. The patients first received four weekly injections administered intradermally followed by monthly booster injections. Peripheral blood mononuclear cells (PBMC) at each vaccination time point were tested in vitro with transfected DC and a panel of 24 overlapping hTERT peptides. In addition, hTERT-specific CD8+ T cells were monitored by pentamer staining. The treatment was well tolerated with minor side effects. Immune responses against telomerase-transfected DC and some of the overlapping hTERT peptides were detected in both patients. We also detected hTERT-specific CD8+ T cells in both patients by pentamer staining in post-vaccination samples. The lung cancer patients obtained a stable disease that lasted 18 months while the patient with pancreas cancer who started the DC vaccination in July 2007 following palliative chemotherapy, still is in stable disease by continuously boost vaccination. T-cell responses against telomerase epitopes have also been identified in both non-vaccinated cancer patients and cancer patients previously vaccinated with telomerase peptide. Since patients with these findings often show extraordinary clinical courses of their disease we hypothesize that it exists a high degree of immunogenicity and HLA promiscuity for some telomerase epitopes. In this study we have shown that vaccination with hTERT-mRNA transfected DC is safe and able to induce robust immune responses to several telomerase T-cell epitopes both in CD4+ and CD8+ T cells. This opens up the possibility for a broad clinical application of mRNA hTERT DC vaccines. Furthermore, responding T cells identified in these patients are strong candidates for T-cell receptor cloning and the receptors identified can thereafter be transferred into T cells creating the next generation of immuno-gene therapy with retargeted T cells. Disclosures: No relevant conflicts of interest to declare.

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Comparative analysis of human immune responses following SARS-CoV-2 vaccination with BNT162b2, mRNA-1273, or Ad26.COV2.S

10.1101/2021.09.21.21262927 ◽

2021 ◽

Author(s):

Dominique J. Barbeau ◽

Judith M. Martin ◽

Emily Carney ◽

Emily Dougherty ◽

Joshua D. Doyle ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Cell Response ◽

T Cell Responses ◽

Neutralizing Antibody ◽

T Cell Response ◽

Virus Neutralization ◽

Cell Responses ◽

Humoral Responses ◽

Prospective Longitudinal

AbstractBackgroundThree SARS-CoV-2 vaccines, two based on mRNA, BNT162b2 and mRNA-1273, and one based on an adenovirus platform, Ad26.COV2.S, received emergency use authorization by the U.S. Food and Drug Administration in 2020/2021. These vaccines displayed clinical efficacy in initial studies against confirmed COVID-19 of 95.0%, 94.1%, and 66.9%, respectively.MethodsIndividuals receiving one of these vaccines were invited to participate in a prospective longitudinal comparative study of immune responses elicited by the three vaccines. In this observational cohort study, humoral responses were evaluated using a SARS-CoV-2 receptor-binding domain (RBD) ELISA and a SARS-CoV-2 virus neutralization assay at mean of 21-31 days and 45-63 days following each initial vaccination. IFN-γ ELISPOT assays were conducted with peripheral blood mononuclear cells obtained at a median of 45-63 days after each initial vaccination.ResultsThe two mRNA-based platforms elicited similar RBD ELISA responses and neutralizing antibody responses. The adenovirus-based vaccine elicited significantly lower RBD ELISA and SARS-CoV-2 virus neutralization activity. The mRNA-1273 vaccine elicited significantly higher spike glycoprotein-specific T cell responses than either the BNT162b2 or the Ad26.COV2.S vaccines.ConclusionsBoth mRNA based vaccines elicited higher magnitude humoral responses than Ad26.COV2.S and mRNA1273 elicited the highest magnitude of T cell response. Neutralizing antibody titers correlated with reported estimates of vaccine efficacy.Summary of key pointsWe compared antigen specific humoral and T cell responses following vaccination with BNT162b2, mRNA-1273, or Ad26.COV2.S. Both mRNA based vaccines elicited higher magnitude humoral responses than Ad26.COV2.S and mRNA1273 elicited the highest magnitude of T cell response.

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A Novel Anti-PD-L1 Vaccine for Cancer Immunotherapy and Immunoprevention

Cancers ◽

10.3390/cancers11121909 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1909 ◽

Cited By ~ 1

Author(s):

Jie Chen ◽

Hui Liu ◽

Tiffany Jehng ◽

Yanqing Li ◽

Zhoushi Chen ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Cancer Patients ◽

Tumor Cells ◽

Tumor Regression ◽

Critical Role ◽

T Cell Responses ◽

The United States ◽

Tumor Vaccines ◽

Cell Responses

Dendritic cells (DCs) are potent antigen-presenting cells that play a critical role in activating cellular and humoral immune responses. DC-based tumor vaccines targeting tumor-associated antigens (TAAs) have been extensively tested and demonstrated to be safe and potent in inducing anti-TAA immune responses in cancer patients. Sipuleucel-T (Provenge), a cancer vaccine of autologous DCs loaded with TAA, was approved by the United States Food and Drug Administration (FDA) for the treatment of castration-resistant prostate cancer. Sipuleucel-T prolongs patient survival, but has little or no effect on clinical disease progression or biomarker kinetics. Due to the overall limited clinical efficacy of tumor vaccines, there is a need to enhance their potency. PD-L1 is a key immune checkpoint molecule and is frequently overexpressed on tumor cells to evade antitumor immune destruction. Repeated administrations of PD-L1 or PD-1 antibodies have induced sustained tumor regression in a fraction of cancer patients. In this study, we tested whether vaccinations with DCs, loaded with a PD-L1 immunogen (PDL1-Vax), are able to induce anti-PD-L1 immune responses. We found that DCs loaded with PDL1-Vax induced anti-PD-L1 antibody and T cell responses in immunized mice and that PD-L1-specific CTLs had cytolytic activities against PD-L1+ tumor cells. We demonstrated that vaccination with PDL1-Vax DCs potently inhibited the growth of PD-L1+ tumor cells. In summary, this study demonstrates for the first time the principle and feasibility of DC vaccination (PDL1-Vax) to actively induce anti-PD-L1 antibody and T cell responses capable of inhibiting PD-L1+ tumor growth. This novel anti-PD-L1 vaccination strategy could be used for cancer treatment and prevention.

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A vaccinia-based vaccine (TroVax) targeting the oncofetal antigen 5T4 administered before and after surgical resection of colorectal cancer liver metastases: Phase II trial

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.2574 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 2574-2574 ◽

Cited By ~ 3

Author(s):

A. Dangoor ◽

D. Burt ◽

R. Harrop ◽

N. Drury ◽

C. Hamer ◽

...

Keyword(s):

Colorectal Cancer ◽

T Cell ◽

Immune Responses ◽

Liver Metastases ◽

Cancer Patients ◽

Colorectal Liver Metastases ◽

T Cell Responses ◽

Cell Responses ◽

T Cell Infiltration ◽

Colorectal Cancer Patients

2574 Background: Oncofetal antigen 5T4 is expressed by most colorectal cancers. Administration of a vaccine combining a Modified Vaccinia Ankara (MVA) vector with 5T4 elicits immune responses in late-stage colorectal cancer patients. This trial seeks to investigate the immunological effects of the vaccine both in peripheral blood and locally in tumour tissue resected during potentially curative surgery for colorectal liver metastases. Some patients may have micrometastatic disease, a potential target for immunotherapy. Methods: Colorectal cancer patients selected for resection of liver metastases were eligible. Recruitment of up to 20 patients was planned. Following screening they received 2 vaccinations prior to, and 2 after, surgery. Primary endpoint was assessment of the immune response at time of surgery. Blood was taken for analysis at screening and 2 weeks after each vaccination. A tumour biopsy was obtained at surgery. T-cell responses were assessed using proliferation and gamma-interferon ELISPOT assays; ELISA used to assess serological response. Immunohistochemical analysis was used to confirm tumour antigen expression and the nature of T-cell infiltration into the liver. If 5T4-specific immune responses were demonstrated patients were offered further vaccinations at 20 and 28 weeks post surgery. Results: Of 20 patients recruited, 16 were eligible for assessment, 4 excluded, 1 due to hepatocellular carcinoma, 3 with inoperable disease. There was no grade III/IV toxicity related to vaccination. Tumour expression of 5T4 was confirmed in all cases, local T-cell infiltration consisted predominantly of CD4 cells. According to proliferation assays, 8 of 16 patients had T-cell responses at time of surgery and 12 of 16 in total to date. 14 patients have developed 5T4-specific antibody responses. At median follow up of 8.4 months 7 of 16 patients have disease recurrence. Conclusions: The MVA-5T4 vaccine (TroVax) was safe and well tolerated in all patients undergoing resection of colorectal liver metastases. 5T4 specific cellular and/or humoral immune responses were induced in the majority of patients following vaccination with TroVax. [Table: see text]

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Analysis of PSA-Specific T-Cell Responses of Prostate Cancer Patients Given a PSA-Based Vaccine on a Clinical Trial

10.21236/ada428064 ◽

2003 ◽

Cited By ~ 1

Author(s):

James Gulley ◽

William Dahut ◽

Philip M. Arlen ◽

Kwong Tsang ◽

Jeffrey Schlom

Keyword(s):

Prostate Cancer ◽

Clinical Trial ◽

T Cell ◽

Cancer Patients ◽

T Cell Responses ◽

Cell Responses

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413 GEN-009, a personalized neoantigen vaccine, elicits robust immune responses in individuals with advanced or metastatic solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0413 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A438-A438

Author(s):

Mara Shainheit ◽

Devin Champagne ◽

Gabriella Santone ◽

Syukri Shukor ◽

Ece Bicak ◽

...

Keyword(s):

Clinical Trial ◽

T Cells ◽

T Cell ◽

Immune Responses ◽

Solid Tumors ◽

Ex Vivo ◽

T Cell Responses ◽

Checkpoint Blockade ◽

T Cell Subsets ◽

Cell Responses

BackgroundATLASTM is a cell-based bioassay that utilizes a cancer patient‘s own monocyte-derived dendritic cells and CD4+ and CD8+ T cells to screen their mutanome and identify neoantigens that elicit robust anti-tumor T cell responses, as well as, deleterious InhibigensTM.1 GEN-009, a personalized vaccine comprised of 4–20 ATLAS-identified neoantigens combined with Hiltonol®, harnesses the power of neoantigen-specific T cells to treat individuals with solid tumors. The safety and efficacy of GEN-009 is being assessed in a phase 1/2a clinical trial (NCT03633110).MethodsA cohort of 15 adults with solid tumors were enrolled in the study. During the screening period, patients received standard of care PD-1-based immunotherapies appropriate for their tumor type. Subsequently, patients were immunized with GEN-009 with additional doses administered at 3, 6, 12, and 24 weeks. Peripheral blood mononuclear cells (PBMCs) were collected at baseline, pre-vaccination (D1), as well as 29, 50, 92, and 176 days post first dose. Vaccine-induced immunogenicity and persistence were assessed by quantifying neoantigen-specific T cell responses in ex vivo and in vitro stimulation dual-analyte fluorospot assays. Polyfunctionality of neoantigen-specific T cells was evaluated by intracellular cytokine staining. Additionally, potential correlations between the ATLAS-identified profile and vaccine-induced immunogenicity were assessed.ResultsGEN-009 augmented T cell responses in 100% of evaluated patients, attributable to vaccine and not checkpoint blockade. Furthermore, neoantigen-induced secretion of IFNγ and/or TNFα by PBMCs, CD4+, and CD8+ T cells was observed in all patients. Responses were primarily from polyfunctional TEM cells and detectable in both CD4+ and CD8+ T cell subsets. Some patients had evidence of epitope spreading. Unique response patterns were observed for each patient with no apparent relationship between tumor types and time to emergence, magnitude or persistence of response. Ex vivo vaccine-induced immune responses were observed as early as 1 month, and in some cases, persisted for 176 days. Clinical efficacy possibly attributable to GEN-009 was observed in several patients, but no correlation has yet been identified with neoantigen number or magnitude of immune response.ConclusionsATLAS empirically identifies stimulatory neoantigens using the patient‘s own immune cells. GEN-009, which is comprised of personalized, ATLAS-identified neoantigens, elicits early, long-lasting and polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses in individuals with advanced cancer. Several patients achieved clinical responses that were possibly attributable to vaccine; efforts are underway to explore T cell correlates of protection. These data support that GEN-009, in combination with checkpoint blockade, represents a unique approach to treat solid tumors.AcknowledgementsWe are grateful to the patients and their families who consented to participate in the GEN-009-101 clinical trial.Trial RegistrationNCT03633110Ethics ApprovalThis study was approved by Western Institutional Review Board, approval number 1-1078861-1. All subjects contributing samples provided signed individual informed consent.ReferenceDeVault V, Starobinets H, Adhikari S, Singh S, Rinaldi S, Classon B, Flechtner J, Lam H. Inhibigens, personal neoantigens that drive suppressive T cell responses, abrogate protection of therapeutic anti-tumor vaccines. J. Immunol 2020; 204(1 Supplement):91.15.

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Neutrophil subtypes shape HIV-specific CD8 T-cell responses after vaccinia virus infection

npj Vaccines ◽

10.1038/s41541-021-00314-7 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Mauro Di Pilato ◽

Miguel Palomino-Segura ◽

Ernesto Mejías-Pérez ◽

Carmen E. Gómez ◽

Andrea Rubio-Ponce ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Vaccinia Virus ◽

Adaptive Immune System ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Responses ◽

Adaptive Immune

AbstractNeutrophils are innate immune cells involved in the elimination of pathogens and can also induce adaptive immune responses. Nα and Nβ neutrophils have been described with distinct in vitro capacity to generate antigen-specific CD8 T-cell responses. However, how these cell types exert their role in vivo and how manipulation of Nβ/Nα ratio influences vaccine-mediated immune responses are not known. In this study, we find that these neutrophil subtypes show distinct migratory and motility patterns and different ability to interact with CD8 T cells in the spleen following vaccinia virus (VACV) infection. Moreover, after analysis of adhesion, inflammatory, and migration markers, we observe that Nβ neutrophils overexpress the α4β1 integrin compared to Nα. Finally, by inhibiting α4β1 integrin, we increase the Nβ/Nα ratio and enhance CD8 T-cell responses to HIV VACV-delivered antigens. These findings provide significant advancements in the comprehension of neutrophil-based control of adaptive immune system and their relevance in vaccine design.

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Innate cell microenvironments in lymph nodes shape the generation of T cell responses during type I inflammation

Science Immunology ◽

10.1126/sciimmunol.abb9435 ◽

2021 ◽

Vol 6 (56) ◽

pp. eabb9435

Author(s):

Joseph M. Leal ◽

Jessica Y. Huang ◽

Karan Kohli ◽

Caleb Stoltzfus ◽

Miranda R. Lyons-Cohen ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Lymph Nodes ◽

Critical Role ◽

Myeloid Cell ◽

T Cell Responses ◽

Type I ◽

Cell Responses ◽

Inflammatory Monocytes ◽

Cell Effector

Microanatomical organization of innate immune cells within lymph nodes (LNs) is critical for the generation of adaptive responses. In particular, steady-state LN-resident dendritic cells (Res cDCs) are strategically localized to intercept lymph-draining antigens. Whether myeloid cell organization changes during inflammation and how that might affect the generation of immune responses are unknown. Here, we report that during type I, but not type II, inflammation after adjuvant immunization or viral infection, antigen-presenting Res cDCs undergo CCR7-dependent intranodal repositioning from the LN periphery into the T cell zone (TZ) to elicit T cell priming. Concurrently, inflammatory monocytes infiltrate the LNs via local blood vessels, enter the TZ, and cooperate with Res cDCs by providing polarizing cytokines to optimize T cell effector differentiation. Monocyte infiltration is nonuniform across LNs, generating distinct microenvironments with varied local innate cell composition. These spatial microdomains are associated with divergent early T cell effector programming, indicating that innate microenvironments within LNs play a critical role in regulating the quality and heterogeneity of T cell responses. Together, our findings reveal that dynamic modulation of innate cell microenvironments during type I inflammation leads to optimized generation of adaptive immune responses to vaccines and infections.

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Marburg virus survivor immune responses are Th1 skewed with limited neutralizing antibody responses

Journal of Experimental Medicine ◽

10.1084/jem.20170161 ◽

2017 ◽

Vol 214 (9) ◽

pp. 2563-2572 ◽

Cited By ~ 9

Author(s):

Spencer W. Stonier ◽

Andrew S. Herbert ◽

Ana I. Kuehne ◽

Ariel Sobarzo ◽

Polina Habibulin ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Ebola Virus ◽

T Cell Responses ◽

Neutralizing Antibody ◽

Cd8 T Cell ◽

Marburg Virus ◽

Antibody Responses ◽

Cd4 T Cell ◽

Cell Responses

Until recently, immune responses in filovirus survivors remained poorly understood. Early studies revealed IgM and IgG responses to infection with various filoviruses, but recent outbreaks have greatly expanded our understanding of filovirus immune responses. Immune responses in survivors of Ebola virus (EBOV) and Sudan virus (SUDV) infections have provided the most insight, with T cell responses as well as detailed antibody responses having been characterized. Immune responses to Marburg virus (MARV), however, remain almost entirely uncharacterized. We report that immune responses in MARV survivors share characteristics with EBOV and SUDV infections but have some distinct differences. MARV survivors developed multivariate CD4+ T cell responses but limited CD8+ T cell responses, more in keeping with SUDV survivors than EBOV survivors. In stark contrast to SUDV survivors, rare neutralizing antibody responses in MARV survivors diminished rapidly after the outbreak. These results warrant serious consideration for any vaccine or therapeutic that seeks to be broadly protective, as different filoviruses may require different immune responses to achieve immunity.

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Optimized Adenovirus-Antibody Complexes Stimulate Strong Cellular and Humoral Immune Responses against an Encoded Antigen in Naïve Mice and Those with Preexisting Immunity

Clinical and Vaccine Immunology ◽

10.1128/cvi.05319-11 ◽

2011 ◽

Vol 19 (1) ◽

pp. 84-95 ◽

Cited By ~ 6

Author(s):

Jin Huk Choi ◽

Joe Dekker ◽

Stephen C. Schafer ◽

Jobby John ◽

Craig E. Whitfill ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Immune Responses ◽

Neutralizing Antibodies ◽

T Cell Responses ◽

Transduction Efficiency ◽

Virus Antibody ◽

Cell Responses

ABSTRACTThe immune response to recombinant adenoviruses is the most significant impediment to their clinical use for immunization. We test the hypothesis that specific virus-antibody combinations dictate the type of immune response generated against the adenovirus and its transgene cassette under certain physiological conditions while minimizing vector-induced toxicity.In vitroandin vivoassays were used to characterize the transduction efficiency, the T and B cell responses to the encoded transgene, and the toxicity of 1 × 1011adenovirus particles mixed with different concentrations of neutralizing antibodies. Complexes formed at concentrations of 500 to 0.05 times the 50% neutralizing dose (ND50) elicited strong virus- and transgene-specific T cell responses. The 0.05-ND50formulation elicited measurable anti-transgene antibodies that were similar to those of virus alone (P= 0.07). This preparation also elicited very strong transgene-specific memory T cell responses (28.6 ± 5.2% proliferation versus 7.7 ± 1.4% for virus alone). Preexisting immunity significantly reduced all responses elicited by these formulations. Although lower concentrations (0.005 and 0.0005 ND50) of antibody did not improve cellular and humoral responses in naïve animals, they did promote strong cellular (0.005 ND50) and humoral (0.0005 ND50) responses in mice with preexisting immunity. Some virus-antibody complexes may improve the potency of adenovirus-based vaccines in naïve individuals, while others can sway the immune response in those with preexisting immunity. Additional studies with these and other virus-antibody ratios may be useful to predict and model the type of immune responses generated against a transgene in those with different levels of exposure to adenovirus.

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