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.

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

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3557-3557 ◽  
Author(s):  
Joleen Marie Hubbard ◽  
Chiara Cremolini ◽  
Rondell P Graham ◽  
Roberto Moretto ◽  
Jessica L Mitchelll ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Single Dose ◽  
T Cell ◽  
Adverse Events ◽  
Maintenance Therapy ◽  
Metastatic Colorectal Cancer ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Skin Reactions ◽  
Cell Responses

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.

p21-ras-peptide-specific T-cell responses in a patient with colorectal cancer. CD4+ and CD8+ T cells recognize a peptide corresponding to a common mutation (13Gly → Asp)

2007 ◽  
Vol 56 (1) ◽  
pp. 40-45 ◽  
Author(s):  
Beate Fossum ◽  
Tobias Gedde-Dahl ◽  
Jarle Breivik ◽  
Jon Amund Eriksen ◽  
Anne Spurkland ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Common Mutation ◽  
Cell Responses ◽  
P21 Ras

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 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 Low-Dose Cyclophosphamide Induces Antitumor T-Cell Responses, which Associate with Survival in Metastatic Colorectal Cancer

2017 ◽  
Vol 23 (22) ◽  
pp. 6771-6780 ◽  
Author(s):  
Martin Scurr ◽  
Tom Pembroke ◽  
Anja Bloom ◽  
David Roberts ◽  
Amanda Thomson ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Metastatic Colorectal Cancer ◽  
Low Dose ◽  
T Cell Responses ◽  
Cell Responses

scholarly journals Enhanced immunotherapeutic profile of oncolytic virus-based cancer vaccination using cyclophosphamide preconditioning

2020 ◽  
Vol 8 (2) ◽  
pp. e000981
Author(s):  
Jonathan G Pol ◽  
Matthew J Atherton ◽  
Kyle B Stephenson ◽  
Byram W Bridle ◽  
Samuel T Workenhe ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Progression ◽  
Cancer Vaccines ◽  
Low Dose ◽  
T Cell Responses ◽  
Large Tumor ◽  
Cell Responses ◽  
Tumor Bearing ◽  
Control Antigen

Despite a sizeable body of research, the efficacy of therapeutic cancer vaccines remains limited when applied as sole agents. By using a prime:boost approach involving two viral cancer vaccines, we were able to generate large tumor-specific CD8+ T-cell responses in a murine model of disseminated pulmonary melanoma. Significant increases in the number and quality of circulating effector T-cells were documented when low-dose cyclophosphamide (CTX) was administered pre-vaccination to tumor-bearing but not tumor-free hosts. Interestingly, tumor-bearing mice receiving CTX and co-primed with a melanoma differentiation antigen together with an irrelevant control antigen exhibited significantly enhanced immunity against the tumor, but not the control antigen, in secondary lymphoid organs. This result highlighted an increased cancer-specific reactivity of vaccine-induced T-cell responses following CTX preconditioning. Additionally, an acute reduction of the frequency of peripheral regulatory T-cells (Tregs) was noticeable, particularly in the proliferating, presumably tumour-reactive, subset. Enhanced infiltration of lungs with multifunctional T-cells resulted in overt reduction in metastatic burden in mice pretreated with CTX. Despite doubling the median survival in comparison to untreated controls, most vaccinated mice ultimately succumbed to cancer progression. However, preconditioning of the virus-based vaccination with CTX resulted in a remarkable improvement of the therapeutic activity leading to complete remission in the majority of the animals. Collectively, these data reveal how CTX can potentiate specific cellular immunity in an antigen-restricted manner that is only observed in vaccinated tumor-bearing hosts while depleting replicating Tregs. A single low dose of CTX enhances antitumor immunity and the efficacy of this potent prime:boost platform by modulating the kinetics of the vaccine-specific responses. Clinical assessment of CTX combined with next-generation cancer vaccines is indicated.

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