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Project objective: Despite the recent revolution in immune checkpoint inhibitors (ICIs), only modest improvement in overall survival and likely caused by not enough potent cellular immunity among BC patients. Our lab has been focus on inducing cellular immunity against HER2+ BC through vaccination against the tumor-associated antigen HER2. Approximately 20 years ago, we performed an experimental pilot study by administrating HER2 peptide and recombinant protein pulsed dendritic cells (DC vaccine) to six patients with refractory HER2+ advanced or metastatic (stage II (≥ 6 +LN), III, or stage IV) BC. We followed the patients on 2019 found that all of the six patients were still alive, 18 years after vaccination. Their blood sample were analyzed with cytometry by time-of-flight (CyTOF) and found there is a significantly increased presence of CD27 expressing memory T cells in response to HER2 peptide stimulation. Recent report on the SARS-CoV2 mRNA vaccine also suggested that CD27 expressing memory T cells plays a critical role in long-lasting cellular immunity against SARS-CoV2 infection. Therefore, we hypothesized that CD27 plays a critical role in cellular immunity against BC, and the stimulation of CD27 expressing T cells with mAb targeting CD27 significantly increase the cellular immunity triggered by vaccination against tumor-associated antigen. Results: We recapitulate the rise of CD27+ antigen specific T cells among the vaccinated patients using a transgenic mouse model expressing human CD27. When combined the adenoviral-vector based HER2 (Ad-HER2) vaccination with a single dose of human aCD27 antibody (Varlilumab), we found there is a robust increase in the HER2 specific T cells compared to vaccination alone, especially CD27+CD44+ memory CD4 T cells, even after 120 days post vaccination. Using an ICI-insensitive syngeneic HER2+ BC models, we found 50% of mice in the combination group of aCD27 antibody plus Ad-HER2 showed total tumor regression by the end of study. When combined with anti-PD1 antibody, the combination of AdHER2 and Varlilumab leads to total tumor regression in 90% of tumor bearing mice with syngeneic HER2+ BC, indicating that the vaccination against tumor associated antigen HER2 plus anti-CD27 antibody sensitized ICI-insensitive HER2+ BC toward ICI. Conclusions: Our data demonstrates that the administration of anti-CD27 antibody significantly increase the long term presence of CD27+ antigen specific memory T cells after vaccination against tumor associated antigen HER2. As consequence, combination of anti-CD27 with HER2 sensitized the immune unresponsive breast cancer toward anti-PD1 antibody. Our study suggests that the vaccination against tumor-associated antigen with mAb targeting CD27 leads to the robust cellular immunity, which is required for successful ICIs against breast cancer. Citation Format: Bin-Jin Hwang, Erika Crosby, Timothy Trotter, Li-Chung Tsao, Tao Wang, Xiao Yang, Herbert Kim Lyerly, Zachary Hartman. Sensitizing breast cancers to immune checkpoint inhibitors through CD27 agonism and vaccination against tumor-associated antigen [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 696.

Background: The majority of colorectal carcinomas (CRCs) are insensitive to anti-PD-1/PD-L1 immune checkpoint inhibitor (ICI) antibodies. While there are many causes for ICI insensitivity, recent studies suggest that the suppression of innate immunity through a loss of innate immune adaptor expression could be a root cause of this insensitivity and an important factor in the evolution of tumor immunosuppression. Methods: We interrogated mitochondrial antiviral signaling gene (MAVS) expression through bioinformatics analyses of multiple datasets to validate its suppression in clinical samples. We then engineered MAVS expressing tumor cells and tested its ability to elicit innate and adaptive anti-tumor immunity using both in vitro and in vivo approaches, which we then confirmed using MAVS expressing viral vectors. Finally, we observed that MAVS stimulated PD-L1expression in different types of tumor cells and then assessed the combination of PD-L1 ICI antibodies with MAVS tumor expression in vivo. Results: MAVS was significantly downregulated in CRCs, but its re-expression could stimulate broad cellular interferon-related responses, in both murine and patient-derived CRCs. In vivo, local MAVS expression elicited significant anti-tumor responses in both immune-sensitive and insensitive CRC models, through the stimulation of an interferon responsive axis that elicited tumor antigen-specific adaptive immunity. Critically, we found that tumor-intrinsic MAVS expression triggered systemic adaptive immune responses that enabled abscopal CD8+ T cell cytotoxicity against distant CRCs. As MAVS also induced PD-L1 expression, we further found synergistic anti-tumor responses in combination with anti-PD-L1 ICIs. Conclusion: These data demonstrate that intratumoral MAVS expression results in local and systemic tumor antigen-specific T cell responses, which could be combined with PD-L1 ICI to permit effective anti-tumor immunotherapy in ICI resistant cancers. We are further exploring to overcome the ICI insensitivity of other types of solid tumor, with MAVS-delivery strategies other than viral vectors. Citation Format: Bin-Jin Hwang, Li-Chung Tsao, Chaitanya Acharya, Timothy Trotter, Pankaj Agarwal, Tao Wang, Junping Wei, Xiao-Yi Yang, Gang-jun Lei, Takuya Osada, Herbert Kim Lyerly, Michael A. Morse, Zachary Hartman. Sensitizing immune unresponsive colorectal cancers to immune checkpoint inhibitors through MAVS overexpression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3531.

BackgroundThe majority of colorectal carcinomas (CRCs) are insensitive to programmed death protein-1/programmed death-ligand 1 (anti-PD-1/PD-L1) immune checkpoint inhibitor (ICI) antibodies. While there are many causes for ICI insensitivity, recent studies suggest that suppression of innate immune gene expression in tumor cells could be a root cause of this insensitivity and an important factor in the evolution of tumor immunosuppression.MethodsWe first assessed the reduction of mitochondrial antiviral signaling gene (MAVS) and related RIG-I pathway gene expression in several patient RNA expression datasets. We then engineered MAVS expressing tumor cells and tested their ability to elicit innate and adaptive anti-tumor immunity using both in vitro and in vivo approaches, which we then confirmed using MAVS expressing viral vectors. Finally, we observed that MAVS stimulated PD-L1 expression in multiple cell types and then assessed the combination of PD-L1 ICI antibodies with MAVS tumor expression in vivo.ResultsMAVS was significantly downregulated in CRCs, but its re-expression could stimulate broad cellular interferon-related responses, in both murine and patient-derived CRCs. In vivo, local MAVS expression elicited significant anti-tumor responses in both immune-sensitive and insensitive CRC models, through the stimulation of an interferon responsive axis that provoked tumor antigen-specific adaptive immunity. Critically, we found that tumor-intrinsic MAVS expression triggered systemic adaptive immune responses that enabled abscopal CD8 +T cell cytotoxicity against distant CRCs. As MAVS also induced PD-L1 expression, we further found synergistic anti-tumor responses in combination with anti-PD-L1 ICIs.ConclusionThese data demonstrate that intratumoral MAVS expression results in local and systemic tumor antigen-specific T cell responses, which could be combined with PD-L1 ICI to permit effective anti-tumor immunotherapy in ICI resistant cancers.

Primary cardiac lymphoma (PCL) is defined as a non-Hodgkin lymphoma involving only the heart or pericardium. PCL is extremely rare and often misdiagnosed. We report the case of a healthy 53-year-old male who originally presented with blurred vision secondary to a right intraocular mass. Enucleation of the eye confirmed a ciliary body melanoma and, upon further investigation, the patient was discovered to have a mass in the right atrium suspicious for a myxoma. However, resection of the atrial mass revealed a low-grade B-cell PCL. The occurrence of PCL in an immunocompetent patient being investigated for a visceral malignancy makes this a highly unusual presentation of a rare neoplasm.