A phase I study of PolyPEPI1018 vaccine plus maintenance therapy in patients with metastatic colorectal cancer with a predictive biomarker (OBERTO).

3557 Background: The goal of this study was to evaluate the safety, tolerability and immunogenicity of a single dose of PolyPEPI1018 as an add-on to maintenance therapy in subjects with metastatic colorectal cancer (mCRC). PolyPEPI1018 is a peptide vaccine containing 12 unique epitopes derived from 7 conserved cancer testis antigens (CTAs) frequently expressed in mCRC. These epitopes were designed to be Personal EPItopes (PEPIs), i.e. predicted by our novel PEPI test to bind to at least three autologous HLA alleles and more likely to induce T-cell responses than epitopes presented by a single HLA. Methods: mCRC patients in the first line setting received the vaccine (dose: 0.2 mg/peptide) just after the transition to maintenance therapy with a fluoropyrimidine and bevacizumab. Vaccine-specific T-cell responses were first predicted by the PEPI test (using the patient’s complete HLA genotype and antigen expression rate) and then measured by ELISpot after one cycle of vaccination. Results: Eleven patients were vaccinated with PolyPEPI1018. The most common adverse events were transient skin reactions (local inflammation at the site of the injections, e.g. erythema, redness and itchiness) and flu-like syndrome. No grade 3 or higher adverse events related to the vaccine occurred. Initial analysis on 4 patients demonstrated that T-cell responses were elicited by 96% of vaccine peptides. The overall percentage agreement between PEPI test-predicted and Elispot-measured CD8+ T cell responses was 71%, consistent with our retrospective analysis on 64 vaccine clinical trials involving 1,790 patients. Two of these 4 patients had unexpected tumor size reduction. Based on these encouraging results, the trial was amended to administer 3 doses of PolyPEPI1018 given 12 weeks apart. Conclusions: PolyPEPI1018 combined with maintenance therapy was safe and well-tolerated in mCRC patients. Unprecedented immune responses were induced after single dose, with broad CRC-specific T cell responses and high accuracy prediction of CD8+ T cell responses. This promising activity in mCRC patients led to a trial amendment to administer 3 doses of PolyPEPI1018 in combination with systemic therapy. Clinical trial information: NCT03391232.

Download Full-text

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

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.065 ◽

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.

Download Full-text

Induction of antigen-specific CD4- and CD8-mediated T-cell responses by fusions of autologous dendritic cells and metastatic colorectal cancer cells

International Journal of Cancer ◽

10.1002/ijc.21184 ◽

2005 ◽

Vol 117 (4) ◽

pp. 587-595 ◽

Cited By ~ 27

Author(s):

Shigeo Koido ◽

Eiichi Hara ◽

Akira Torii ◽

Sadamu Homma ◽

Yoichi Toyama ◽

...

Keyword(s):

Colorectal Cancer ◽

Dendritic Cells ◽

T Cell ◽

Metastatic Colorectal Cancer ◽

Cancer Cells ◽

T Cell Responses ◽

Cell Responses ◽

Colorectal Cancer Cells

Download Full-text

Identification of a neo-epitope dominating endogenous CD8 T cell responses to MC-38 colorectal cancer

OncoImmunology ◽

10.1080/2162402x.2019.1673125 ◽

2019 ◽

Vol 9 (1) ◽

pp. 1673125 ◽

Cited By ~ 3

Author(s):

Brett J. Hos ◽

Marcel G.M. Camps ◽

Jitske van den Bulk ◽

Elena Tondini ◽

Thomas C. van den Ende ◽

...

Keyword(s):

Colorectal Cancer ◽

T Cell ◽

T Cell Responses ◽

Cd8 T Cell ◽

Cell Responses

Download Full-text

Safety and immunogenicity of the Ad26.COV2.S COVID-19 vaccine candidate: interim results of a phase 1/2a, double-blind, randomized, placebo-controlled trial

10.1101/2020.09.23.20199604 ◽

2020 ◽

Cited By ~ 10

Author(s):

Jerry Sadoff ◽

Mathieu Le Gars ◽

Georgi Shukarev ◽

Dirk Heerwegh ◽

Carla Truyers ◽

...

Keyword(s):

Single Dose ◽

T Cell ◽

Adverse Events ◽

Dose Level ◽

Phase 1 ◽

T Cell Responses ◽

Cell Responses ◽

Grade 3 ◽

Efficacious Vaccine ◽

Dose Levels

BACKGROUND The ongoing coronavirus disease (COVID)-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be controlled by an efficacious vaccine. Multiple vaccines are in development, but no efficacious vaccine is currently available. METHODS We designed a multi-center phase 1/2a randomized, double-blinded, placebo-controlled clinical study to assesses the safety, reactogenicity and immunogenicity of Ad26.COV2.S, a non-replicating adenovirus 26 based vector expressing the stabilized pre-fusion spike (S) protein of SARS-CoV-2. Ad26.COV2.S was administered at a dose level of 5x1010 or 1x1011 viral particles (vp) per vaccination, either as a single dose or as a two-dose schedule spaced by 56 days in healthy adults (18-55 years old; cohort 1a & 1b; n= 402 and healthy elderly >65 years old; cohort 3; n=394). Vaccine elicited S specific antibody levels were measured by ELISA and neutralizing titers were measured in a wild-type virus neutralization assay (wtVNA). CD4+ T-helper (Th)1 and Th2, and CD8+ immune responses were assessed by intracellular cytokine staining (ICS). RESULTS We here report interim analyses after the first dose of blinded safety data from cohorts 1a, 1b and 3 and group unblinded immunogenicity data from cohort 1a and 3. In cohorts 1 and 3 solicited local adverse events were observed in 58% and 27% of participants, respectively. Solicited systemic adverse events were reported in 64% and 36% of participants, respectively. Fevers occurred in both cohorts 1 and 3 in 19% (5% grade 3) and 4% (0% grade 3), respectively, were mostly mild or moderate, and resolved within 1 to 2 days after vaccination. The most frequent local adverse event (AE) was injection site pain and the most frequent solicited AEs were fatigue, headache and myalgia. After only a single dose, seroconversion rate in wtVNA (50% inhibitory concentration - IC50) at day 29 after immunization in cohort 1a already reached 92% with GMTs of 214 (95% CI: 177; 259) and 92% with GMTs of 243 (95% CI: 200; 295) for the 5x1010 and 1x1011vp dose levels, respectively. A similar immunogenicity profile was observed in the first 15 participants in cohort 3, where 100% seroconversion (6/6) (GMTs of 196 [95%CI: 69; 560]) and 83% seroconversion (5/6) (GMTs of 127 [95% CI: <58; 327]) were observed for the 5x1010 or 1x1011 vp dose level, respectively. Seroconversion for S antibodies as measured by ELISA (ELISA Units/mL) was observed in 99% of cohort 1a participants (GMTs of 528 [95% CI: 442; 630) and 695 (95% CI: 596; 810]), for the 5x1010 or 1x1011 vp dose level, respectively, and in 100% (6/6 for both dose levels) of cohort 3 with GMTs of 507 (95% CI: 181; 1418) and 248 (95% CI: 122; 506), respectively. On day 14 post immunization, Th1 cytokine producing S-specific CD4+ T cell responses were measured in 80% and 83% of a subset of participants in cohort 1a and 3, respectively, with no or very low Th2 responses, indicative of a Th1-skewed phenotype in both cohorts. CD8+ T cell responses were also robust in both cohort 1a and 3, for both dose levels. CONCLUSIONS The safety profile and immunogenicity after only a single dose are supportive for further clinical development of Ad26.COV2.S at a dose level of 5x1010 vp, as a potentially protective vaccine against COVID-19. Trial registration number: NCT04436276

Download Full-text

NY-ESO-1 Vaccination in Combination with Decitabine for Patients with MDS Induces CD4+ and CD8+ T-Cell Responses

Blood ◽

10.1182/blood.v126.23.2873.2873 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2873-2873 ◽

Cited By ~ 1

Author(s):

Pragya Srivastava ◽

Junko Matsuzaki ◽

Benjamin E. Paluch ◽

Zachary Brumberger ◽

Stephanie Kaufman ◽

...

Keyword(s):

T Cell ◽

Adverse Events ◽

Promoter Methylation ◽

Cell Response ◽

Research Funding ◽

T Cell Responses ◽

Cd8 T Cell ◽

T Cell Response ◽

Cd4 T Cell ◽

Cell Responses

Abstract Background: Identification of suitable target antigens for immunotherapy has been a challenge in patients with myeloid malignancies. NY-ESO-1 has been identified as an immunotherapeutic target in solid tumors. Its use in myeloid cancer is limited due to silencing by dense promoter hypermethylation. We and others have demonstrated that decitabine can induce expression of NY-ESO-1 in leukemia cell lines. We hypothesized that vaccination against NY-ESO-1 in combination with decitabine would be safe and result in NY-ESO-1 expression sufficient to induce NY-ESO-1 specific humoral and cellular immune responses in treatment-na•ve myelodysplastic syndrome (MDS) patients. Methods: We performed a phase I trial of NY-ESO-1 vaccine (anti-DEC-205-NY-ESO-1 fusion protein (CDX-1401) with poly-ICLC adjuvant; Celldex Therapeutics) in combination with decitabine (20 mg/m2/day x 5 days). Patients with intermediate/high-risk MDS by IPSS, > 18 years old, ECOG performance status < 2, and adequate hepatic and renal function were enrolled on an IRB-approved protocol (median age 64y). Patients with uncontrolled medical illness, HIV-positivity, auto-immunity or recent corticosteroid/radiation therapy were excluded. All patients signed informed consent and were treated in accordance with the Declaration of Helsinki. Patients were vaccinated on day -14, received decitabine on day 1 and were re-vaccinated on day 14 of each cycle. Four cycles of therapy were planned. Peripheral blood was obtained pre-treatment, twice weekly, and at end of treatment (EOT). CD11b+ myeloid cells were isolated from each sample. Immune monitoring was performed at baseline and at EOT. An interim analysis, pre-specified in the protocol for the first 6 patients, was planned for safety and immunology endpoints. Three additional patients enrolled to an expansion cohort to ensure sufficient power for correlative studies remain on treatment. Results: Analysis of the initial safety cohort showed no unexpected toxicities. The most frequent adverse events were related to decitabine and included cytopenias (predominantly grades 3/4), elevated liver enzymes (grade 3), fatigue (grade 2), edema (grade 2/3) and diarrhea (grade 1/2). Two patients did not complete four cycles of therapy due to serious adverse events; 1 patient with a history of myocardial infarction (MI) developed in-stent restenosis and recurrent MI; a second patient suffered a terminal intracranial hemorrhage due to thrombocytopenia (deemed decitabine related). LINE-1 (surrogate for global methylation) and NY-ESO-1 promoter methylation in the CD11b+ myeloid population were serially quantified for the first 2 patients by bisulfite pyrosequencing. The methylation nadir for LINE-1 and NY-ESO-1 occurred between days 8 and 15 of each decitabine cycle. Changes in LINE-1 and NY-ESO-1 methylation were correlated for each patient (R2 = 0.95, p < 0.001). Expression of NY-ESO-1 mRNA (by nested RT-PCR) was performed on CD11b+ cells from days 0, 8, 15, and 22 of the first cycle for these two patients. Patient 1 exhibited NY-ESO-1 mRNA on days 8 and 15. Patient 2 did not show any NY-ESO-1 expression. Of the first 6 patients analyzed, none showed baseline humoral immunity to NY-ESO-1 and seroconversion was observed in one subject (Table 1). Five patients had induced NY-ESO-1 specific CD4+ T-cell responses and 4 patients had NY-ESO-1 specific CD8+ T-cell responses following vaccination. Table 1. Response to Vaccination. T cell response assessed by ELISPOT for IFN-g and scored after subtracting background. Numbers in parentheses indicate number of epitopes recognized by T cells. Bold type indicates responses induced or enhanced by vaccination. Patient ID Antibody response CD4+ T cell response CD8+ T cell response Pre Post Pre Post Pre Post 1 - + ++ (2) +++ (3) - (0) + (1) 2 - - - (0) + (2) - (0) - (0) 3 - - - (0) + (2) - (0) + (1) 4 - - - (0) + (1) - (0) - (0) 5 - - - (0) + (1) - (0) + (2) 6 - - + (1) - (0) - (0) ++ (3) Conclusion: Vaccination against NY-ESO-1 is safe in combination with decitabine. Circulating myeloid cells exhibited decreased NY-ESO-1 promoter methylation. 1 of 2 sampled patients demonstrated induction of NY-ESO-1 mRNA in the myeloid compartment. Vaccination successfully induced CD4+ and CD8+ T-cell responses in a majority of patients. These data indicate that vaccination against NY-ESO-1 in combination with decitabine is feasible, opening the door for future studies targeting this induced antigen in MDS. Disclosures Wang: Immunogen: Research Funding. Griffiths:Celgene: Honoraria; Alexion Pharmaceuticals: Honoraria; Astex: Research Funding.

Download Full-text