scholarly journals MHC-restricted phosphopeptide antigens: preclinical validation and first-in-humans clinical trial in participants with high-risk melanoma

2020 ◽  
Vol 8 (1) ◽  
pp. e000262 ◽  
Author(s):  
Victor H Engelhard ◽  
Rebecca C Obeng ◽  
Kara L Cummings ◽  
Gina R Petroni ◽  
Angela L Ambakhutwala ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mass Spectrometry ◽  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Adverse Events ◽  
T Cell Responses ◽  
Breast Cancer Cell Lines ◽  
Cell Responses ◽  
Phosphorylated Peptides

BackgroundPhosphorylated peptides presented by MHC molecules represent a new class of neoantigens expressed on cancer cells and recognized by CD8 T-cells. These peptides are promising targets for cancer immunotherapy. Previous work identified an HLA-A*0201-restricted phosphopeptide from insulin receptor substrate 2 (pIRS2) as one such target. The purpose of this study was to characterize a second phosphopeptide, from breast cancer antiestrogen resistance 3 (BCAR3), and to evaluate safety and immunogenicity of a novel immunotherapic vaccine comprising either or both of these phosphorylated peptides.MethodsPhosphorylated BCAR3 protein was evaluated in melanoma and breast cancer cell lines by Western blot, and recognition by T-cells specific for HLA-A*0201-restricted phosphorylated BCAR3 peptide (pBCAR3126-134) was determined by51Cr release assay and intracellular cytokine staining. Human tumor explants were also evaluated by mass spectrometry for presentation of pIRS2 and pBCAR3 peptides. For the clinical trial, participants with resected stage IIA–IV melanoma were vaccinated 6 times over 12 weeks with one or both peptides in incomplete Freund’s adjuvant and Hiltonol (poly-ICLC). Adverse events (AEs) were coded based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V.4.03, with provision for early study termination if dose-limiting toxicity (DLT) rates exceeded 33%. The enrollment target was 12 participants evaluable for immune response to each peptide. T-cell responses were assessed by interferon-γ ELISpot assay.ResultspBCAR3 peptides were immunogenic in vivo in mice, and in vitro in normal human donors, and T-cells specific for pBCAR3126-134controlled outgrowth of a tumor xenograft. The pIRS21097-1105peptide was identified by mass spectrometry from human hepatocellular carcinoma tumors. In the clinical trial, 15 participants were enrolled. All had grade 1 or 2 treatment-related AEs, but there were no grade 3–4 AEs, DLTs or deaths on study. T-cell responses were induced to the pIRS21097-1105peptide in 5/12 patients (42%, 90% CI 18% to 68%) and to the pBCAR3126-134peptide in 2/12 patients (17%, 90% CI 3% to 44%).ConclusionThis study supports the safety and immunogenicity of vaccines containing the cancer-associated phosphopeptides pBCAR3126-134and pIRS21097-1105, and the data support continued development of immune therapy targeting phosphopeptides. Future studies will define ways to further enhance the magnitude and durability of phosphopeptide-specific immune responses.Trial registration numberNCT01846143

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

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.

443 An immunotherapy trio in advanced HNSCC for coordinated B and T cell antigen response

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A469-A469
Author(s):  
Bernard Fox ◽  
Tarsem Moudgil ◽  
Traci Hilton ◽  
Noriko Iwamoto ◽  
Christopher Paustian ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Data Sets ◽  
Cell Responses ◽  
Anti Cancer ◽  
Bead Arrays ◽  
Hnscc Cell

BackgroundOutcomes for recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are dismal and responses to anti-PD-1 appear best in tumors with PD-1+ T cells in proximity to PD-L1+ cells, arguing that improved outcome is associated with a pre-existing anti-cancer immune response. Based on this, we hypothesize that vaccines which prime and/or expand T cells to a spectrum of antigens overexpressed by HNSCC combined with T cell agonists, like anti-GITR, that provide costimulatory signals will improve the anti-PD-1 response rates. We have developed a cancer vaccine, DPV-001, that contains more than 300 proteins for genes overexpressed by HNSCC, encapsulated in a CLEC9A-targeted microvesicle and containing TLR/NOD agonists and DAMPs. Recently, we reported that combining anti-GITR + vaccine + anti-PD-1 augmented therapeutic efficacy in a preclinical model and now plan a phase 1b trial of this combination in patients with advanced HNSCC.MethodsSera from patients receiving DPV-001 as adjuvant therapy for definitively treated NSCLC, were analyzed for IgG responses to human proteins by MAP bead arrays and results compared to TCGA gene expression data sets for HNSCC. HNSCC cell lines were evaluated by RNASeq and peptides were eluted from HLA, analyzed by mass spectroscopy and correlated against MAP bead arrays and TCGA data sets. Tumor-reactive T cells from a vaccinated patient were enriched and expanded, and used in cytokine release assay (CRA) against autologous NSCLC and partially HLA matched allogeneic HNSCC cell lines.ResultsPatients receiving DPV-001 (N=13) made 147 IgG responses to at least 70 proteins for genes overexpressed by HNSCC. Preliminary evaluation of the HNSCC peptidome against the results of MAP bead array identify antigens that are target of a humoral immune response. Additionally, tumor-reactive T cells from DPV-001 vaccinated patient recognize two partially HLA-matched HNSCC targets, but not a mis-matched target.ConclusionsRecent observations from our lab and others have correlated IgG Ab responses with T cell responses to epitopes of the same protein. Based on the data summarized above, we hypothesize that we have induced T cell responses against a broad spectrum of shared cancer antigens that are common among adenocarcinomas and squamous cell cancers. Our planned clinical trial will vaccinate and boost the induced responses by costimulation with anti-GITR and then sequence in delayed anti-PD-1 to relieve checkpoint inhibition. MAP bead arrays and the peptidome library generated above will be used to assess anti-cancer B and T cell responses.Trial RegistrationNCT04470024Ethics ApprovalThe original clinical trial was approved by the Providence Portland Medical Center IRB, approval # 13-046. The proposed clinical trial has not yet been reviewed by the IRB.

scholarly journals 65 Identification of frequently presented non-mutated tumor-specific immunogens for the development of both off-the-shelf and personalized vaccines without need for tumor biopsy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A72-A72
Author(s):  
Orsolya Lorincz ◽  
Levente Molnar ◽  
Zsolt Csiszovszki ◽  
Eszter Somogyi ◽  
Jozsef Toth ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Metastatic Colorectal Cancer ◽  
Cancer Vaccines ◽  
T Cell Responses ◽  
Tumor Biopsy ◽  
Cell Responses ◽  
Antigen Selection

BackgroundVaccines have little chance of destroying heterogeneous tumor cells since they rarely induce polyclonal T-cell responses against the tumor. The main challenge is the accurate identification of tumor targets recognizable by T cells. Presently, 6–8% of neoepitopes selected based on the patients‘ tumor biopsies are confirmed as real T cell targets.1 2. To overcome this limitation, we developed a computational platform called Personal Antigen Selection Calculator (PASCal) that identifies frequently presented immunogenic peptide sequences built on HLA-genetics and tumor profile of thousands of real individuals.3 Here we show the performance of PASCal for the identification of both shared and personalized tumor targets in metastatic colorectal cancer (mCRC) and breast cancer subjects.MethodsExpression frequency of the tumor-specific antigens (TSAs) ranked in PASCal’s database (based on 7,548 CRC specimen) was compared to the RNA-sequencing data of CRC tumors obtained from TCGA. Using PASCal, 12 shared PEPIs (epitopes restricted to at least 3 HLA class I alleles of a subject from an in silico cohort) derived from 7 TSAs were selected as frequent targets (calculated probability: average 2.5 [95%CI 2.4–2.8] TSAs/patient). Spontaneous immune responses against each of the twelve 9mer peptides were determined by ELISpot using PBMCs of 10 mCRC subjects who participated in the OBERTO-101 study.4 PEPIs selected for a breast cancer subject based on her HLA genotype were also tested.ResultsEach of the 106 tumors analyzed expressed at least 13, average 15 of the 20 top-ranked TSAs in PASCal’s database confirming their prevalence in CRC. 7/10 subjects had spontaneous CD8+ T-cell responses against at least one peptide selected with PASCal. Each peptide (12/12) was recognized by at least one patient. Patients‘ T-cells reacted with average 3.6/12 (30%) peptides confirming the expression of average 2.8 [95%CI 1.0–4.6] TSAs (n=10). After HLA-matching, among the subjects for whom we could select at least 4 PEPIs (average 5) from the list of 12 peptides (n=6), average 2.5 (50%) peptides were positive. Of the 12 PEPIs selected with PASCal for a breast cancer subject, we detected spontaneous T-cell responses against 9 PEPIs, indicating that at least 75% of the selected peptides were present in the subject’s tumor and were recognized by T-cells.ConclusionsPASCal platform accommodates both tumor- and patient heterogeneity and identifies non-mutated tumor targets that may trigger polyclonal cytotoxic T-cell responses. It is a rapid tool for the design of both off-the-shelf and personalized cancer vaccines negating the need for tumor biopsy.ReferencesWells DK, van Buuren MM, Dang KK, et al. Key parameters of tumor epitope immunogenicity revealed through a consortium approach improve neoantigen prediction. Cell 2020:183(3):818–34.e13.Bulik-Sullivan B, Busby J, Palmer CD, et al. Deep learning using tumor HLA peptide mass spectrometry datasets improves neoantigen identification. Nat Biotech 2018:37:55–63.Somogyi E, Csiszovszki Z, Lorincz O, et al. 1181PDPersonal antigen selection calculator (PASCal) for the design of personal cancer vaccines. Annal Oncol 2019:30(Supplement_5):v480-v81.Hubbard J, Cremolini C, Graham R, et al. P329 PolyPEPI1018 off-the shelf vaccine as add-on to maintenance therapy achieved durable treatment responses in patients with microsatellite-stable metastatic colorectal cancer patients (MSS mCRC). J ImmunoTher Cancer 2019:7(1):282.

Immunotransplant Expands Vaccine-Induced Memory T Cell Responses In Patients With Mantle Cell Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1816-1816 ◽  
Author(s):  
Debra K Czerwinski ◽  
Joshua Brody ◽  
Holbrook E Kohrt ◽  
Malek Faham ◽  
Etelka Gabriel ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Cell Lymphoma ◽  
T Cell Responses ◽  
Blood Samples ◽  
Post Transplant ◽  
Cell Responses ◽  
Mantle Cell ◽  
Over Time

Abstract Background Autologous transplant has been shown to prolong survival in patients with MCL, a disease which is known to have poor long-term survival. The purpose of this clinical trial is to reduce the relapse rate and prolong survival through the induction of anti-tumor T cells which can effectively survey, expand and eradicate tumor cells when and if they arise. In a murine model, T cells from CpG-tumor vaccinated donors were shown to expand preferentially in recipient mice following a myeloablative regimen and were effective in eradicating tumor in these mice (Goldstein, M. et al., Blood 2011). Consequently, we developed a clinical trial where patients with mantle cell lymphoma (MCL) are given a CpG-based cellular vaccine followed by an autologous stem cell transplant (Immunotransplant). T cells, harvested after vaccination prior to transplant, are reinfused post-transplant. Blood samples are taken prior to vaccine, post the initial vaccination, as well as post immunotransplant to study the CD4 and CD8 anti-tumor T cell responses. Blood samples are also drawn pre and 2 weeks post a vaccine boost given approximately 6 months post-transplant to assess the memory component of the anti-tumor T cells. Methods Peripheral blood lymphocytes (PBL) were cultured for 5 days with and without autologous CpG activated tumor. T cells were re-stimulated over-night with fresh activated tumor then analyzed by flow cytometry for phenotype (CD4+ T cells, CD8+/CD56- T cells and memory marker, CD45RO) as well as functionality (cytokine expression [IFN-g, TNF and IL-2], cytolitic activity [perforin and granzyme B expression] and activation markers, CD137 and ICOS [CD278]). In several cases, tumor-responsive T cells from co-cultures were sequenced to determine their TCRb repertoire. Clonotypes enriched over those found in PBL drawn pre-vaccine were deemed to be antigen-specific. These clones were compared to ones enriched directly in the blood after the original vaccine and later boost. Results To date, 21 MCL patients have been enrolled and have received the immunotransplant as well as final vaccine boost. 15 patients have been analyzed and have shown anti-tumor T cell responses following vaccine and immunotransplant. In most cases, the T cell responses were boosted post immunotransplant suggesting an expansion of anti-tumor T cells as predicted by the murine model. The phenotype of the responding T cells (CD4, CD8, or both CD4 and CD8) varied between patients. (Figure 1.) Also, in 11/15 patients, tumor-responsive T cells were still present at the time of the final vaccine, about 6 months post-transplant. The final vaccine boosted T cell responses, mostly in the CD8 compartment, suggesting an induced memory anti-tumor T cell response, which is durable over time. (Figure 2.) Finally, TCRb clonotypic analyses of the responding T cells demonstrated that these T cell clones were enriched in the blood post vaccine providing further proof that they were vaccine-induced. Conclusion Immunotransplant can induce and expand a population of tumor-responsive memory T cells, both CD4 and CD8, which can be detected as an expansion of specific TCRb clonotypes in whole blood. This response is durable over time and can be boosted suggesting a means by which the immune system can be enticed to maintain anti-tumor surveillance and eradicate tumor cells in the future. Disclosures: Faham: Sequenta, Inc.: Employment, Patents & Royalties.

A phase I study to evaluate safety, immunogenicity and anti-tumor activity of the multi-peptide vaccine IMA901 in renal cell carcinoma patients (RCC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5098-5098 ◽  
Author(s):  
M. Staehler ◽  
A. Stenzl ◽  
P. Y. Dietrich ◽  
T. Eisen ◽  
A. Haferkamp ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adverse Events ◽  
Clinical Benefit ◽  
T Cell Responses ◽  
Pharmacokinetic Data ◽  
Multi Centre Study ◽  
Gm Csf ◽  
Cell Responses ◽  
Anti Tumor Activity

5098 Background: IMA901 is a therapeutic cancer vaccine based on multiple synthetic tumor-associated peptides confirmed to be naturally presented by analysis of primary RCC tissues. IMA901 consists of 9 HLA-class I-binding and 1 HLA class II-binding peptides with the capacity to activate cytotoxic T cells (CD8+ T cells) and T helper cells (CD4+ T cells). Methods: 30 patients with stage III/IV RCC were enrolled in a single arm, multi-centre study. The endpoints were safety, T-cell responses, pharmacokinetics of the intradermal application of GM-CSF and anti-tumor activity according to RECIST. Patients had to be HLA-A*02 positive and received 8 intradermal vaccinations on days 1, 2, 3, 8, 15, 22, 36 and 64 each consisting of 4.5 mg IMA901 and 75 μg GM-CSF. Results: The most prevalent adverse events (AEs) were fatigue, cough and headache. Aseptical lymphadenitis and injection site reactions such as erythema, edema and pruritus were the most frequent possibly drug-related AEs. All possibly drug-related adverse events were mild to moderate. No patient experienced any possibly drug-related serious adverse events or deaths during the study. Pharmacokinetic data provided no evidence for accumulation of GM-CSF upon repeated i.d. administration. 74% of patients showed a vaccine-induced specific T-cell response and 30% of patients responded to multiple peptides contained in IMA901. The overall tumor assessment in patients with measurable disease revealed that 8 patients (35%) demonstrated a clinical benefit (1 PR + 7 SD). Most encouraging, patients who elicited multiple T-cell responses showed a statistically significant higher clinical benefit rate. Conclusions: IMA901 is safe, very well tolerated and immunogenic. Clinically observed tumor growth control in RCC patients may imply anti-tumor activity strongly supported by two patients with tumor regression (1 PR and 1 patient with 27% shrinkage in target lesions). The mode of action is strongly supported by the finding that multiple T-cell responders were significantly more likely to have a clinical benefit. These data clearly support the further development of IMA901. No significant financial relationships to disclose.

scholarly journals A transplantable tumor model allowing investigation of NY-BR-1-specific T cell responses in HLA-DRB1*0401 transgenic mice

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Krishna Das ◽  
David Eisel ◽  
Mathias Vormehr ◽  
Karin Müller-Decker ◽  
Adriane Hommertgen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
Cell Line ◽  
In Silico ◽  
Cell Epitope ◽  
Tumor Model ◽  
T Cell Responses ◽  
T Cell Epitope ◽  
Cell Responses

Abstract Background NY-BR-1 has been described as a breast cancer associated differentiation antigen with intrinsic immunogenicity giving rise to endogenous T and B cell responses. The current study presents the first murine tumor model allowing functional investigation of NY-BR-1-specific immune responses in vivo. Methods A NY-BR-1 expressing tumor model was established in DR4tg mice based on heterotopic transplantation of stable transfectant clones derived from the murine H2 compatible breast cancer cell line EO771. Composition and phenotype of tumor infiltrating immune cells were analyzed by qPCR and FACS. MHC I binding affinity of candidate CTL epitopes predicted in silico was determined by FACS using the mutant cell line RMA-S. Frequencies of NY-BR-1 specific CTLs among splenocytes of immunized mice were quantified by FACS with an epitope loaded Db-dextramer. Functional CTL activity was determined by IFNγ catch or IFNγ ELISpot assays and statistical analysis was done applying the Mann Whitney test. Tumor protection experiments were performed by immunization of DR4tg mice with replication deficient recombinant adenovirus followed by s.c. challenge with NY-BR-1 expressing breast cancer cells. Results Our results show spontaneous accumulation of CD8+ T cells and F4/80+ myeloid cells preferentially in NY-BR-1 expressing tumors. Upon NY-BR-1-specific immunization experiments combined with in silico prediction and in vitro binding assays, the first NY-BR-1-specific H2-Db-restricted T cell epitope could be identified. Consequently, flow cytometric analysis with fluorochrome conjugated multimers showed enhanced frequencies of CD8+ T cells specific for the newly identified epitope in spleens of immunized mice. Moreover, immunization with Ad.NY-BR-1 resulted in partial protection against outgrowth of NY-BR-1 expressing tumors and promoted intratumoral accumulation of macrophages. Conclusion This study introduces the first H2-Db-resctricted CD8+ T cell epitope-specific for the human breast cancer associated tumor antigen NY-BR-1. Our novel, partially humanized tumor model enables investigation of the interplay between HLA-DR4-restricted T cell responses and CTLs within their joint attack of NY-BR-1 expressing tumors.

scholarly journals Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancer

2021 ◽  
Vol 9 (5) ◽  
pp. e002254
Author(s):  
Meenal Sinha ◽  
Li Zhang ◽  
Sumit Subudhi ◽  
Brandon Chen ◽  
Jaqueline Marquez ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Clinical Response ◽  
T Cell Responses ◽  
Castration Resistant Prostate Cancer ◽  
Cell Responses ◽  
Castration Resistant ◽  
Clinical Responses

BackgroundSipuleucel-T is a US Food and Drug Administration-approved autologous cellular immunotherapy that improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We examined whether administering ipilimumab after sipuleucel-T could modify immune and/or clinical responses to this treatment.MethodsA total of 50 patients with mCRPC were enrolled into a clinical trial (NCT01804465, ClinicalTrials.gov) where they received ipilimumab either immediately or delayed 3 weeks following completion of sipuleucel-T treatment. Blood was collected at various timepoints of the study. Luminex assay for anti-prostatic acid phosphatase (PAP) and anti-PA2024-specific serum immunoglobulin G (IgG) and ELISpot for interferon-γ (IFN-γ) production against PAP and PA2024 were used to assess antigen-specific B and T cell responses, respectively. Clinical response was defined as >30% reduction in serum prostate-specific antigen levels compared with pretreatment levels. The frequency and state of circulating immune cells were determined by mass cytometry by time-of-flight and statistical scaffold analysis.ResultsWe found the combination to be well tolerated with no unexpected adverse events occurring. The timing of ipilimumab did not significantly alter the rates of antigen-specific B and T cell responses, the primary endpoint of the clinical trial. Clinical responses were observed in 6 of 50 patients, with 3 having responses lasting longer than 3 months. The timing of ipilimumab did not significantly associate with clinical response or toxicity. The combination treatment did induce CD4 and CD8 T cell activation that was most pronounced with the immediate schedule. Lower frequencies of CTLA-4 positive circulating T cells, even prior to treatment, were associated with better clinical outcomes. Interestingly, these differences in CTLA-4 expression were associated with prior localized radiation therapy (RT) to the prostate or prostatic fossa. Prior radiation treatment was also associated with improved radiographic progression-free survival.ConclusionCombining CTLA-4 blockade with sipuleucel-T resulted in modest clinical activity. The timing of CTLA-4 blockade following sipuleucel-T did not alter antigen-specific responses. Clinical responses were associated with both lower baseline frequencies of CTLA-4 expressing T cells and a history of RT. Prior cancer therapy may therefore result in long-lasting immune changes that influence responsiveness to immunotherapy with sipuleucel-T and anti-CTLA-4.

scholarly journals P04.02 Diversity of CD4+ blood T-cell clonality predicts longer survival with CTLA4 or PD-1 checkpoint inhibition in advanced melanoma

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A17.1-A17
Author(s):  
A Arakawa ◽  
S Vollmer ◽  
J Tietze ◽  
A Galinski ◽  
MV Heppt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adverse Events ◽  
T Cell Responses ◽  
T Cell Clones ◽  
Cell Responses ◽  
Cell Clones ◽  
Clinical Responses ◽  
Melanoma Patients ◽  
Research Grant

BackgroundT cells play a central role in tumor immunity. In principle, T cell requires antigen recognition by T-cell receptor (TCR) to gain effector function. Antigen-driven activation leads to clonal T-cell expansion with generation of progeny cells that all express the same chronotypic TCR. This makes TCR analysis a useful tool to comprehensively and individually understand antigen-specific T-cell responses. Indeed, we previously showed that the TCR repertoires of CD8+ T cells but not CD4+ T cells are restricted with many clones in the blood of psoriasis patients. Together with the strong genetic association to HLA-C*06:02 causing an autoimmune CD8+ T-cell response against melanocytes in psoriasis, our results from TCR analyses clearly indicate an autoimmune pathogenesis of psoriasis.Patients and MethodsHere, we utilize our expertise to understand how anti-tumor T-cell responses affect clinical responses and immune-related adverse events (irAEs) in therapeutic checkpoint inhibitions. We analyzed melanoma patients upon the therapeutic blockade of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) or programmed cell death 1 (PD-1) using TCR Vβ-gene spectratyping.ResultsSurprisingly, we observed variable levels of restriction in CD4+ and extensive restrictions in CD8+ T-cell repertoires in the blood of melanoma patients compared to healthy controls. This indicates the presence of a substantial numbers of CD4+ and CD8+ T-cell clones in the blood prior to the initiation of immunotherapy. The clones detected in the blood were enriched in tumor-infiltrating lymphocytes (TILs). This suggests that melanoma-reactive T-cell clones circulate more frequently in melanoma patients, although it is generally assumed that tumor-specific T-cell clones are only detectable in TILs. Greater diversification particularly in CD4+ blood T-cell clones before immunotherapy correlated with long-term survival after CTLA4 or PD-1 inhibition. In patients who developed severe immune-related adverse events (irAEs) during CTLA4 blockade, we detected newly expanded blood T-cell clones, suggesting that newly emerged T-cell responses contributed to these irAEs.ConclusionsOur data demonstrate that the diversity of T-cell clones in the circulation may reflect the anti-melanoma responses. This study provides a rationale for predicting clinical responses to checkpoint inhibitors using patient’s blood, and also emphasizes importance of CD4+ T cell-mediated anti-tumor immunity in melanoma.Disclosure InformationA. Arakawa: None. S. Vollmer: None. J. Tietze: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; BMS. D. Speakers Bureau/Honoraria (speakers bureau, symposia, and expert witness); Modest; BMS, MSD, Novartis, Roche, Almiral. A. Galinski: None. M.V. Heppt: None. C. Berking: B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; Amgen, AstraZeneca, BMS, Incyte, Merck, MSD, Novartis, Pierre Fabre, Regeneron, Roche, Sanofi/Aventis. J.C. Prinz: None.

A phase I study of the safety and immunogenicity of a multi-peptide personalized genomic vaccine in the adjuvant treatment of solid tumors and hematological malignancies.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14307-e14307
Author(s):  
Ana Blazquez ◽  
Alex Rubinsteyn ◽  
Julia Kodysh ◽  
John Patrick Finnigan ◽  
Thomas Urban Marron ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Phase I ◽  
Adjuvant Treatment ◽  
Phase I Study ◽  
Hematological Malignancies ◽  
Ex Vivo ◽  
T Cell Responses ◽  
Cell Responses

e14307 Background: Mutation-derived tumor antigens (MTAs) arise as a direct result of somatic variations that occur during carcinogenesis and can be characterized via genetic sequencing and used to identify MTAs. We developed a platform for a fully-personalized MTA-based vaccine in the adjuvant treatment of solid and hematological malignancies. Methods: This is a single-arm, open label, proof-of-concept phase I study designed to test the safety and immunogenicity of Personalized Genomic Vaccine 001 (PGV001) that targets up to 10 predicted personal tumor neoantigens based on patient’s HLA profile (ClinicalTrials.gov: NCT02721043). Results: Patients who completed vaccination with PGV001_002 (head and neck squamous cell cancer) received 10 doses of vaccine comprising 10 long peptides (LP) combined with poly-ICLC (toll-like receptor-3 agonist) intradermally. Vaccine-induced T-cell responses were determined at weeks 0 and 27 (before and after treatment, respectively), ex vivo by interferon (IFN)-g enzyme-linked immunospot assay and after expansion by intracellular cytokine staining. Overlapping 15-mer peptides (OLPs) spanning the entirety of each LP and 9-10-mer peptides corresponding to each predicted class I epitope (Min) were pooled. Ex vivo responses to these peptide pools were undetectable at week 0 but were evident at week 27 against 2 OLPs out of 10 (20%) and in 5 Min out of 10 (50%). After in vitro expansion, neoantigen-specific CD4+ and CD8+ T-cell responses were found in 5 out of 10 pooled peptides (50%). 7 out of 10 (70%) epitopes elicited polyfunctional T-cell responses (secretion of INF-g, TNF-a, and/or IL-2) from either CD4+ or CD8+ T cells. Conclusions: The PGV001 vaccine in our first patient showed both safety and immunogenicity, eliciting CD4+ and CD8+ responses to the vaccine peptides. As we enroll additional patients in this clinical trial, and perform deeper phenotyping of their tumor-reactive T cells, we will learn the determinants necessary for the successful generation of MTA-based vaccines, while informing future immunotherapeutic approaches and rational combinations. Clinical trial information: NCT02721043.

scholarly journals Identification of Naturally Processed Mumps Virus Epitopes by Mass Spectrometry: Confirmation of Multiple CD8+ T-Cell Responses in Mumps Patients

2019 ◽  
Author(s):  
Jelle de Wit ◽  
Maarten E Emmelot ◽  
Hugo Meiring ◽  
Jacqueline A M van Gaans-van den Brink ◽  
Cécile A C M van Els ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Mumps Virus ◽  
T Cell Response ◽  
T Cell Epitopes ◽  
Cell Responses

Abstract Background The re-emergence of mumps among vaccinated young adults has become a global issue. Besides waning of antibody responses, suboptimal induction of T-cell responses may reduce protection. In a recent study, we observed a dominant polyfunctional CD8+ T-cell response after natural mumps virus (MuV) infection that was not present after vaccination. Unraveling the MuV epitope repertoire can provide insight in the specificity, functionality, and breadth of the T-cell response against MuV. Methods Peptides were eluted from human leukocyte antigen (HLA) class I molecules of MuV-infected cells and characterized by advanced mass spectrometry. Selected identified MuV peptides were tested for in vitro and ex vivo immunogenicity. Results In this study, we identified a broad landscape of 83 CD8+ T-cell epitopes of MuV, 41 of which were confirmed based on synthetic peptide standards. For 6 epitopes, we showed induction of an HLA-A*02-restriced CD8+ T-cell response. Moreover, robust T-cell responses against 5 selected MuV epitopes could be detected in all tested mumps patients using peptide/HLA-A*02:01 dextramers. Conclusions The identified CD8+ T-cell epitopes will help to further characterize MuV-specific T-cell immunity after natural MuV infection or vaccination. These MuV epitopes may provide clues for a better understanding of, and possibly for preventing, mumps vaccine failure. We identified for the first time 41 mumps virus (MuV)-specific HLA-A*02 epitopes. For 6 epitopes, CD8+ T-cell responses were confirmed in T cells derived from several mumps cases, and MuV-specific CD8+ T cells could be identified by peptide/dextramer staining.

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