Shared Tumor Associated Antigens Research Articles

Abstract LB346: Mapping of shared tumor antigen reactivity with nanoparticle encapsulated mRNA in prostate cancer patients

Abstract Background: Prostate cancer (PC) remains refractory immune checkpoint therapies (CPT) despite having an FDA-approved cancer vaccine. PC is known to have a low mutation burden resulting in low level of neoantigens, so shared tumor associated antigens (TAAs) and translocations presumably represent a dominant source of antigens in this disease. While PC is thought to be a poorly immunogenic tumor, the frequency and breadth of tumor antigen reactivity in PC patients is unclear. Methods: We utilized novel programmable immunogenic mRNA nanoparticle platform and created formulations encoding a range of full-length prostate TAAs (TAAmRNA) to systemically study T cell immune responses to across a range of TAAs in PC patients. We administered 8 PC TAAmRNAs (NY-ESO-1, HK2, STEAP1, TMPRSS2-ERG, PAP, PSA, PSCA and PSMA) to in-vitro cultured peripheral blood mononuclear cells (PBMC) from 43 treatment-naïve localized PC patients compared to 17 age-matched non-cancer control patients. We assessed upregulation of early T cell activation markers and interferon-gamma (INFg) cytokine production through flow cytometry and ELISPOT, respectively. Results: 20% of PC patients possessed TAA-specific CD8+ T cell responses to at least one antigen. NY-ESO-1, HK2 and TMPRSS2-ERG had the highest T cell recall responses at an average of 35%, with NY-ESO-1 demonstrating the strongest responses per patient. Of the patients that respond to any given TAA, 47% of patients responded to three or more antigens, with 11% of PC patients responding to all TAAs. PC patients also showed heightened production of IFNg, with 35% of patients showing pan-responsiveness to three or more antigens. Particularly, HK2 stimulated the highest levels of INFg production. These levels of responsiveness are not seen in the control cohort. Conclusions: Encapsulated mRNA nanoparticles can be used to systematically map antigen reactivity across a cohort of cancer patients and reveal frequent pan-responsiveness to multiple TAAs in what has considered to be an immunologically cold cancer These results also reveal a hierarchy in immunogenicity of candidates that can enable future vaccine development. Continual efforts to assess the immunogenicity of shared PC TAAs in more advanced disease, and how patient responses to TAAs are modulated by immunotherapies, can aid in refining combinatorial therapies for PC. Citation Format: Elena Montauti, Ole Haabeth, Chris Rae, Samuel Deutsch, Lawrence Fong, David Oh. Mapping of shared tumor antigen reactivity with nanoparticle encapsulated mRNA in prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB346.

Eliciting an immune-mediated antitumor response through oncolytic herpes simplex virus-based shared antigen expression in tumors resistant to viroimmunotherapy

BackgroundOncolytic virotherapy (OV) is an immunotherapy that incorporates viral cancer cell lysis with engagement of the recruited immune response against cancer cells. Pediatric solid tumors are challenging targets because they...

T cell recognition of novel shared breast cancer antigens is frequently observed in peripheral blood of breast cancer patients

ABSTRACTAdvances within cancer immunotherapy have fueled a paradigm shift in cancer treatment, resulting in increasing numbers of cancer types benefitting from novel treatment options. Despite originally being considered an immunologically silent malignancy, recent studies encourage the research of breast cancer immunogenicity to evaluate immunotherapy as a treatment strategy. However, the epitope landscape in breast cancer is minimally described, limiting the options for antigen-specific, targeted strategies. Aromatase, never in mitosis A-related kinase 3 (NEK3), protein inhibitor of activated STAT3 (PIAS3), and prolactin are known as upregulated proteins in breast cancer. In the present study, these four proteins are identified as novel T cell targets in breast cancer.From the four proteins, 147 peptides were determined to bind HLA-A*0201 and -B*0702 using a combined in silico/in vitro affinity screening. T cell recognition of all 147 peptide-HLA-A*0201/-B*0702 combinations was assessed through the use of a novel high-throughput method utilizing DNA barcode labeled multimers.T cell recognition of sequences within all four proteins was demonstrated in peripheral blood of patients, and significantly more T cell responses were detected in patients compared to healthy donors for both HLA-A*0201 and -B*0702. Notably, several of the identified responses were directed toward peptides, with a predicted low or intermediate binding affinity. This demonstrates the importance of including low-affinity binders in the search for epitopes within shared tumor associated antigens (TAAs), as these might be less subject to immune tolerance mechanisms.The study presents four novel TAAs containing multiple possible targets for immunotherapy of breast cancer.

Personalized Neo-Epitope Vaccines for Cancer Treatment.

After more than a century of efforts to establish cancer immunotherapy in clinical practice, the advent of checkpoint inhibition (CPI) therapy was a critical breakthrough toward this direction (Hodi et al. in Cell Rep 13(2):412-424, 2010; Wolchok et al. in N Engl J Med 369(2):122-133, 2013; Herbst et al. in Nature 515(7528):563-567, 2014; Tumeh et al. in Nature 515(7528):568-571, 2014). Further, CPIs shifted the focus from long studied shared tumor-associated antigens to mutated ones. As cancer is caused by mutations in somatic cells, the concept to utilize these correlates of 'foreignness' to enable recognition and lysis of the cancer cell by T cell immunity seems an obvious thing to do.

Abstract LB-076: Personal neoantigen immunotherapy in hepatocellular carcinoma

Abstract Hepatocellular carcinoma (HCC) is one of the most common cancers and the leading causes of mortality in China with limited therapeutic options. To investigate whether neoantigens could induce tumor specific immune responses in patients with HCC, neoantigen stimulating cellular therapy (neo-MASCT) was applied after radical resection. Neo-MASCT was a cell-based immunotherapy with injections of mature dendritic cells (DCs) loaded with a peptide pool of multiple shared tumor associated antigens (TAAs) and several personalized neoantigens followed by autologous T cells stimulated by these DCs. To obtain neoantigens, fresh tumor samples were acquired immediately after biopsy or surgery for subsequently WES and RNAseq. All mutations including SNV, non-frame shift insert/deletion (Indel), and neoORF were detected by comparing NGS data from tumors to normal tissues. All neo-epitope candidates were predicted by our own proprietary algorithm MASNEO according to the patient’s HLA class I genotypes. Long neoantigen peptides containing 25-31 amino acids with higher affinities were selected for further synthesis and treatment. Peptides containing multiple neo-epitopes were preferred. Until now, eight patients had received neo-MASCT, and seven of them were tested for specific immune responses against both TAAs and neoantigens using IFNγ Elispot assay. The results showed that Neo-MASCT induced TAA-specific immune responses in five patients (5/7, 71%), and induced neoantigen-specific immune responses in six patients (6/7, 86%), respectively. One patient demonstrated specific T cell responses against all the five neoantigen peptides (5/5, 100%) after neo-MASCT treatment. The average responsive rate of neoantigens was 65% (22/34 peptides) in the six responding patients. In conclusion, our results demonstrate that neo-MASCT is well-tolerated in HCC patients and elicits immune responses against multiple tumor antigens, especially personalized neoantigens. We will continuously monitor the immune responses against neoantigens, and use the results to train and optimize our predicting algorithm. We will also evaluate the clinical benefit of neo-MASCT in further clinical trials with more patients. Citation Format: Sui Peng, Zhenwei Peng, Lixia Xu, Jie Mei, Longqing Tang, Yanyan Han, Ming Kuang. Personal neoantigen immunotherapy in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-076.

Abstract B129: Human endogenous retroviruses as a potential reservoir for T-cell mediated cancer immunotherapy

Abstract Epigenetic modulation using DNA methyltransferase inhibitors (DNMTis), such as 5-azacytidine (5-aza-CR), have been shown to affect the cellular immunogenicity in vitro through upregulations of human endogenous retroviruses (HERV) leading to activation of the INFγ response pathway. HERVs comprise up to 8% of the human genome, and may hold a large reservoir of potential tumor antigens.We examined the in vivo efficacy of 5-aza-CR in terms of upregulations of HERV expression during standard treatment regimen, as well as the ability of such HERV transcripts to form T-cell antigens leading to measurable T-cell recognition upon treatment. We have studied 66 HERV genes that have been shown to be transcribed in human tissues. To identify HERV derived immune recognition, we generated a library of 1169 HERV derived potential antigenic peptides restricted to most abundant MHC class I molecules in the Caucasian population. Peripheral blood mononuclear cells (PBMCs) from a cohort of 19 patients and bone marrow samples from a cohort of 11 patients, treated with DNMTis for different hematological malignancies (MDS, AML, and CMML) were used to detect CD8+ T-cells reactive to ERV-derived peptides. We detected CD8+ T-cells specific to several HERV-derived peptides both in healthy and diseased individuals. Further, in an additional cohort of patients we examined expression level of these HERVs by RNA seq analysis and compared with healthy individuals demonstrating a disease associated upregulation of HERVs in hematological malignancies. Presence of T-cells reactive to HERV antigens and enhanced expression of HERVs in these malignancies suggest that HERVs may indeed provide a pool of shared tumor associated antigens. These antigens could potentially be enhanced through DNMTi treatment and may provide a target for T-cell mediated immunotherapy. Citation Format: Sunil Kumar Saini, Anne-Mette Bjerregaard, Andreas D. Ørskov, Ashwin Unnikrishnan, Staffan Holmberg, Govardhan Anande, Amalie Kai Bentzen, Zoltan Szallasi, Aron C. Eklund, Kirsten Grønbæk, Sine Reker Hadrup. Human endogenous retroviruses as a potential reservoir for T-cell mediated cancer immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B129.

Abstract IA11: Deciphering the immunobiology of ovarian cancer to create effective immunotherapy.

Abstract Deep interrogations of the immunological landscape of human ovarian cancer has revealed the importance of the immune system in tumor control. In particular, the finding that intratumoral accumulation of tumor-infiltrating lymphocytes (TILs) is associated with improved survival in ovarian and various other cancer types supports the notions that spontaneously-arising T-cells with antitumor activity reside in cancer and control tumor outgrowth, and that this prognostic biomarker can be reinforced though administration of immunotherapy. Since this association was first described more than a decade ago, more sophisticated analyses have refined our understanding of the complex interplay between ovarian cancer cells and the host immune system. This includes the recent elucidation of a phenotypically-defined subset of ovarian cancer associated TILs that exhibit specific reactivity against autologous tumor cells, which represent a potential source for tumor-reactive T cell for use in the adoptive immunotherapy of ovarian cancer. Additionally, the discovery that the antigenic repertoire recognized by TILs is comprised of both shared tumor associated antigens and patient specific neo-antigens derived from mutated self-proteins uniquely expressed by the ovarian cancer cell has rationalized the clinical testing of highly personalized vaccines. While induction of patient-specific T cell responses holds significant promise, further analysis has revealed that the ovarian cancer microenvironment harbors a myriad of immunosuppressive factors that have the potential to thwart otherwise effective T cell responses. Ovarian cancer cells downregulate the expression of molecules associated with immune recognition and preferentially recruit inhibitory cells such as regulatory T cells to the tumor site. Ovarian cancer cells also express multiple negative immunoregulatory ligands that interact with reciprocal receptors expressed preferentially by the subset of tumor-reactive T cells and thereby limit their activity, however, with a new cadre of antibodies that effective block these axes of immunosuppression, clinical trials are underway to determine the efficacy of this form of passive immunomodulation and encouraging results are emerging. Taken together, detailed exploration of the immunobiology of the ovarian cancer microenvironment has increased our understanding of the roles of the cellular and molecular elements that influence tumor outgrowth. This knowledge serves as a roadmap for the rational development of effective immunotherapeutic approaches in ovarian cancer. Citation Format: Daniel J. Powell, Jr. Deciphering the immunobiology of ovarian cancer to create effective immunotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA11.

TCL1: a shared tumor-associated antigen for immunotherapy against B-cell lymphomas

AbstractImmunotherapy with therapeutic idiotype vaccines offers promise for treatment of B-cell malignancies. However, identification of novel immunogenic lymphoma-associated antigens that are universally expressed is necessary to overcome the barriers of patient-specific idiotype vaccines. Here, we determined whether T-cell leukemia/lymphoma 1 (TCL1) oncoprotein encoded by the TCL1 gene could be a target for immunotherapy of B-cell malignancies. We show that TCL1 mRNA and protein are selectively expressed in normal B cells but markedly hyperexpressed in multiple human B-cell lymphomas, including follicular lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, and splenic marginal zone B-cell lymphoma. We demonstrated that TCL1-specific CD8+ T cells can be generated from HLA-A*0201 (HLA-A2)+ normal donors and identified TCL171-78 (LLPIMWQL) as the minimal epitope recognized by these T cells. More importantly, TCL171-78 peptide-specific T cells were present in the peripheral blood and tumor-infiltrating lymphocytes of lymphoma patients, could be expanded in vitro, and lysed autologous tumor cells but not normal B cells in an HLA-A2–restricted manner. Our results suggest that TCL1 is naturally processed and presented on the surface of lymphoma cells for recognition by cytotoxic T cells and can serve as a novel target for development of immunotherapeutic strategies against common B-cell lymphomas.

TCL1: A Shared Tumor-Associated Antigen for Immunotherapy Against B-Cell Lymphomas

Abstract 105Rituximab-based chemotherapy regimens have improved complete response rates, progression-free survival, and overall survival of B-cell non-Hodgkin lymphoma patients. However, most patients relapse and die of their lymphoma. To further improve clinical outcome, novel strategies that eradicate minimal residual disease (MRD) after induction therapy are needed. Therapeutic vaccines may induce antitumor antibody and T-cell responses and may eradicate MRD by complementary mechanisms. A recent randomized phase III clinical trial showed that patient-specific idiotype vaccination improves disease-free survival when administered in the setting of MRD in follicular lymphoma (FL), providing proof of principle that therapeutic vaccines can improve clinical outcome (Schuster et al, J Clin Oncol, 2011). However, generation of a custom-made vaccine formulation for each patient can be expensive and time consuming. To overcome these difficulties, identification of novel shared lymphoma-associated antigens is necessary.The T-cell leukemia/lymphoma 1 (TCL1) oncoprotein encoded by the TCL1 gene is a co-activator of Akt and promotes cell proliferation and survival. Ectopic expression of TCL1 in B cells in transgenic mice results in the development of B-cell malignancies and TCL1 was reported to be aberrantly expressed in multiple human B cell malignancies. Here, we determined whether TCL1 can serve as a novel shared tumor-associated antigen in B cell lymphomas. We analyzed the expression pattern of TCL1 in human B cell lymphomas and normal tissues by real-time PCR, flow cytometry, immunohistochemistry, and Western blotting. TCL1 mRNA transcripts were hyperexpressed in multiple types of primary B cell lymphomas [chronic lymphocytic leukemia (CLL), n=7; mantle cell lymphoma (MCL), n=6; FL, n=12, diffuse large B-cell lymphoma (DLBCL), n=5] as compared with B cells derived from normal donors. TCL1 mRNA was not detected in other normal tissues that included T cells, adipose tissue, esophagus, ovary, spleen, bladder, heart, placenta, brain, kidney, prostate, liver, muscle, thyroid, colon, lung, intestine, trachea, thymus, and cervix. Very low TCL1 mRNA was detected in testis. By flow cytometry, immunohistochemistry, and/or Western blotting we observed that the TCL1 protein is hyperexpressed in CLL, MCL, DLBCL, Burkitts lymphoma, and FL, but not splenic marginal zone lymphoma. To determine whether TCL1 is immunogenic, we synthesized overlapping 15-mer peptides spanning the entire length of the TCL1 protein and stimulated PBMC from HLA-A*0201+ (HLA-A2+) normal donors to generate peptide-specific T cells. We found that TCL165–79 peptide (TQIGPSLLPIMWQLY) consistently induced T cells that secreted significant amount of IFN-γ from 3 normal donors. By intracellular cytokine assay, we determined that the TCL165–79 peptide-specific IFN-g was produced by CD8+ T cells but not CD4+ T cells. Using a panel of peptide-pulsed EBV-transformed B-cell lines that were mismatched at the MHC Class I locus and MHC Class I blocking antibodies, we determined that HLA-A2 is the restriction element of the TCL165–79 peptide-specific T cells. Consistent with this, TCL165–79 peptide-specific CD8+ T cells lysed TCL1 expressing HLA-A2+ MCL cell lines but did not lyse, TCL1 expressing HLA-A2− myeloma cell line. Using a panel of peptides truncated progressively by one amino acid at the N- and C-termini of the TCL165–79peptide, we determined that TCL171–78(LLPIMWQL) is the minimal epitope that bound to HLA-A2. Furthermore, cytotoxic T lymphocytes (CTL) specific to this peptide efficiently killed lymphoma cell lines and primary lymphoma cells from CLL, MCL, DLBCL, and FL in an HLA-A2-restricted manner. Using TCL171–78 peptide-specific HLA-A2 tetramers, we found that TCL1 epitope-specific CTLs were present in the peripheral blood and/or tumor-infiltrating lymphocytes of B-cell lymphoma patients (n=8). More importantly, these TCL1 epitope-specific CTLs could be expanded in vitro and lysed autologous and allogeneic tumor cells in an HLA-A2-restricted manner. In conclusion, our results suggest that TCL1 is naturally processed and presented on the surface of primary lymphoma cells for recognition by CTL and can serve as a novel, shared tumor-associated antigen for therapeutic vaccine development against common B-cell lymphomas including CLL, MCL, DLBCL, and FL. Disclosures:Neelapu:Biovest International, Inc.: Research Funding.

The shared tumor associated antigen cyclin‐A2 is recognized by high‐avidity T‐cells

Cyclin-A2, a key cell cycle regulator, has been shown to be overexpressed in various types of malignancies with little expression in normal tissue. Such tumor-associated genes potentially are useful targets for cancer immunotherapy. However, high-avidity cyclin-specific T cells are considered to be thymically deleted. We identified at least one nonameric HLA-A*0201 binding cyclin-A2 epitope by a reverse immunology approach. Using a highly efficient T-cell expansion system that is based on CD40-activated B (CD40-B) cells as sole antigen-presenting cells we successfully generated cyclin-A2 specific CTL from HLA-A*0201(+) donors. Interestingly, high-avidity cyclin-A2 specific CTL lines, which recognized peptide-pulsed and antigen expressing target cells, were indeed generated by stimulation with CD40-B cells when pulsed with low concentrations of peptide, whereas CD40-B cells pulsed at saturating concentrations could only induce low-avidity CTL, which recognized peptide-pulsed target cells only. One high-avidity CTL line was subcloned and CTL clones, whose peptide concentration required for half-maximal lysis were less than 1 nM, could lyse cyclin-A2 expressing tumor cells. Taken together, cyclin A2 is an attractive candidate for immune intervention in a significant number of cancer patients and high-avidity T cells can be readily generated using CD40-B cells as antigen-presenting cells.

Identification of human autologous cytotoxic T-lymphocyte-defined osteosarcoma gene that encodes a transcriptional regulator, papillomavirus binding factor.

The prognosis for patients with osteosarcoma who do not respond to current chemotherapy protocols still remains poor. Toward the goal of establishing efficacious peptide-based immunotherapy for those patients, we previously developed an autologous pair of CTLs and an osteosarcoma cell line. In the current study, we screened the cDNA library of this osteosarcoma cell line using an autologous CTL clone and identified cDNA encoding an antigen. The isolated cDNA was identical to papillomavirus binding factor (PBF), which was recently reported as a DNA binding transcription factor cooperating with RUNX1. Reverse transcription-PCR analysis revealed that PBF was expressed in 16 of 19 cases of bone and soft-tissue sarcoma cell lines (5 of 6 of osteosarcoma lines) and 57 of 76 sarcoma tissue samples (11 of 14 of osteosarcoma tissues). Also, PBF was expressed in 10 of 13 epithelial cancer cell lines and 20 of 34 of cancer tissues. In contrast, PBF was detected in some normal organs including ovary, pancreas, spleen, and liver by reverse transcription-PCR but was restricted in the cytoplasm by immunostaining and undetectable by Western blotting. Furthermore, a 12-mer peptide, CTACRWKKACQR, located at the COOH terminus of PBF, was found to be a minimum requirement for recognition by the CTL clone in the context of the HLA-B*5502 molecule. These findings suggest that PBF is a shared tumor-associated antigen, which may serve as a source of peptides applicable to peptide-based immunotherapy for osteosarcoma and other malignant tumors.

Survivin is a shared tumor-associated antigen expressed in a broad variety of malignancies and recognized by specific cytotoxic T cells

AbstractSurvivin, a member of the inhibitor of apoptosis protein family, is expressed in almost all types of malignancies, making this protein a useful tool for the development of broadly applicable vaccination therapies. We used a recently identified HLA-A2 binding peptide and dendritic cells (DCs) from healthy donors to induce survivin-specific cytotoxic T lymphocytes (CTLs) in vitro. These T cells efficiently lysed target cells pulsed with the cognate peptide. Furthermore, survivin-specific CTLs recognized HLA-A2–matched tumor cell lines and primary malignant cells from patients with leukemia in an antigen-specific and HLA-restricted manner as demonstrated with the use of cold target inhibition assays and blocking antibodies. To validate the immunogenicity of survivin we performed the experiments in an autologous setting and used monocyte-derived DCs as targets. Interestingly, we found that DCs up-regulate survivin expression on stimulation with tumor necrosis factor α (TNF-α). However, these mature DCs were not recognized by survivin-specific CTLs, whereas they lysed autologous mature DCs pulsed with the antigenic peptide or transfected with whole tumor RNA purified from a survivin-expressing cell line. To further analyze the possible use of survivin-specific CTLs in cancer therapies, we induced survivin-specific CTLs using peripheral blood mononuclear cells (PBMNCs) and DCs from a patient with chronic lymphocytic leukemia (CLL). The in vitro–generated T cells efficiently recognized autologous malignant CLL cells, whereas they spared autologous-purified nonmalignant B cells or DCs. Our results demonstrate that survivin epitopes are presented on a broad variety of malignancies and can be applied in vaccination therapies.

The HER2/neu-derived peptide p654-662 is a tumor-associated antigen in human pancreatic cancer recognized by cytotoxic T lymphocytes.

The protooncogene HER2/neu encodes a 185-kDa transmembrane protein with extensive homology to the epidermal growth factor receptor. It is overexpressed in several human cancers of epithelial origin, such as pancreatic cancer. Previously, we demonstrated that cytotoxic T lymphocytes (CTL) derived from breast, ovarian, and non-small cell lung cancer recognized a peptide derived from HER2/neu. To evaluate whether this HLA-A2-binding peptide is a tumor-associated antigen (TAA) in pancreatic cancer, the ability of HER2/neu-reactive CTL to lyse human pancreatic carcinoma cells was tested. CTL were generated from tumor-associated T lymphocytes from HLA-A2+ HER2/neu+ breast and ovarian cancer patients. All CTL recognized autologous and allogeneic HER2/ neu+ tumor cells in an HLA-A2-restricted fashion. Furthermore, all CTL recognized p654-662 (GP2) derived from HER2/neu. These CTL also recognized HER2/neu+ pancreatic cancer cells in an HLA-A2-restricted fashion. HER2/neu+ HLA-A2- pancreatic cancer were not or only poorly lysed. Repeated stimulation of HLA-A2+ PBL from pancreatic cancer patients using the HER2/neu-derived peptide resulted in specific recognition of this peptide and, more importantly, HER2/neu+ pancreatic tumors in an HLA-A2-restricted fashion. Autologous HLA-A2+ fibroblasts or HLA-A2+ malignant melanoma cells were not recognized. HLA-A2- peptide-stimulated T lymphocytes showed no significant cytotoxicity. These results demonstrate that this HER2/neu-derived peptide is a shared TAA among several adenocarcinomas including pancreatic carcinoma, suggesting a common mechanism of recognition of these human tumors by T lymphocytes. The identification of the HER2/neu-derived peptide GP2 as a TAA in pancreatic cancer provides an opportunity for the design of novel immunotherapy and vaccine strategies.