Relative Immunological Effectiveness (RIE) of Carbon Ion Radiation Therapy for Pancreatic Cancer

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Principal Investigator: Chandan  Guha
Organization: ALBERT EINSTEIN COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $458,589
Funding agency: National Cancer Institute

Abstract
Pancreatic cancer is the leading cause of cancer-related death with less than 5% (5-year) survival rate with
current treatment regimen involving chemo-radiation therapy. Almost all patients with pancreatic cancer
eventually develop metastatic disease with poor prognosis for survival. There remains a significant opportunity
for breakthrough strategies to improve the quality of life and outcomes for pancreatic cancer patients. Recent
studies have shown some success with proton therapy and the interest in proton RT has grown progressively
with increasing evidence indicating substantial benefit over photons (XRT). The success of proton therapy relies
on precise delivery of high dose in tumor tissue, sparing normal tissue due to the nature of its Bragg’s peak,
while maintaining similar therapeutic advantages as XRT. Carbon ion radiation therapy (CIRT) offers steep
Bragg’s peak and less scatter but also higher LET (Linear Energy Transfer), resulting in greater ionizing events
and greater biological damage. We hypothesize that greater complex DNA damage also defined as relative
biological effect (RBE) of CIRT can induce stronger immune response. In the current proposal, we are testing
the hypothesis that high-LET CIRT has unique ability of enhancing tumor immune response, when applied alone
or combine with other immunotherapeutic agents. Our goal is to determine the immunomodulation effectiveness
of CIRT compared to XRT in pancreatic cancer mouse model. We will test the effect of high LET-CIRT on tumor
cells as well as the immune cells at local and systemic level. We will correlate biological end points such as DNA
double strand breaks (DSB), complex DNA damage and clonogenic survival in XRT/CIRT-irradiated cells with
their ability to induce immune response under aim 1. We will also determine whether HDAC inhibition enhances
antigen presentation by pancreatic tumor cells in aim 2. Under aim 3, we will enhance the efficacy of CIRT by
reprogramming tumor microenvironment (TME) using concurrent treatment with check point inhibitors and
antigen presentation activators.
Relevance. Successful completion of these studies could establish the significance and help us design unique
combination therapy of immunotherapy with CIRT for solid tumors.

Terms: <Ablation><Actinotherapy><Address><Anti-CD40><Antibodies><Antigen Presentation><Biologic Relative Effectiveness><Biological><Bp50><C57BL/6 Mouse><CD40><CDW40><Cancer Cause><Cancer Etiology><Cancer Patient><Cancers><Carbon><Carbon ion><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell surface><Cells><Cessation of life><Characteristics><Class I Antigens><Class I Genes><Class I Major Histocompatibility Antigens><Clinical><Co-culture><Cocultivation><Coculture><Coculture Techniques><Combination immunotherapy><Combined Modality Therapy><Complex><Complex Class 1><DNA><DNA Damage><DNA Double Strand Break><DNA Injury><DNA Viruses><Death><Deoxyribonucleic Acid><Disease><Disorder><Disseminated Malignant Neoplasm><Distant Cancer><Distant Metastasis><Dose><Effectiveness><Engineering><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Event><Experimental Designs><Exposure to><Fire - disasters><Fires><GEM model><GEMM model><Genetically Engineered Mouse><Goals><H+ element><HDAC><HDAC Agent><HDAC Proteins><HDAC inhibitor><Heavy Ions><High Linear Energy Transfer Radiation><High-LET Radiation><Histocompatibility Antigens Class I><Histone Deacetylase><Histone Deacetylase Inhibitor><Histone deacetylase inhibition><Hydrogen Ions><Immune><Immune Evasion><Immune mediated therapy><Immune response><Immunes><Immunity><Immunochemical Immunologic><Immunocompetent><Immunologic><Immunological><Immunological response><Immunologically><Immunologically Directed Therapy><Immunologics><Immunomodulation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapeutic agent><Immunotherapy><In Vitro><Infiltration><Innate Immunity><Interferon Type I><Intracellular Communication and Signaling><Irradiated tumor><Light Therapy><Linear Energy Transfer><Local Therapy><Localized Therapy><MGC9013><MHC Class I><MHC Class I Genes><MHC Class I Molecule><MHC Class I Protein><MHC class I antigen><Major Histocompatibility Complex Class 1><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Measurement><Measures><Metastasis><Metastasize><Metastatic Cancer><Metastatic Lesion><Metastatic Malignant Neoplasm><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methods><Mice><Mice Mammals><Modality><Modeling><Molecular><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Myeloid Cells><Native Immunity><Natural Immunity><Nature><Neoplasm Metastasis><Non-Specific Immunity><Nonspecific Immunity><Normal Tissue><Normal tissue morphology><Organ><Outcome><PD 1><PD-1><PD-1 antibody><PD1><PD1 antibody><Pancreas Cancer><Pancreas Neoplasms><Pancreas Tumor><Pancreatic Cancer><Pancreatic Tumor><Patients><Pattern><Photons><Photoradiation Therapy><Phototherapy><Prediction of Response to Therapy><Proteins><Protons><QOL><Quality of life><Radiation><Radiation therapy><Radio><Radiotherapeutics><Radiotherapy><Randomization trial><Relative Biological Effectiveness><Reporting><Roentgen Rays><Roentgenotherapy><Role><Secondary Neoplasm><Secondary Tumor><Signal Transduction><Signal Transduction Systems><Signaling><Solid Neoplasm><Solid Tumor><Splenocyte><Survival Rate><System><T-Cell Activation><T-Cells><T-Lymphocyte><TNFRSF5><TNFRSF5 gene><Techniques><Testing><Therapeutic><Travel><Treatment Protocols><Treatment Regimen><Treatment Schedule><Treatment outcome><Tumor Antigens><Tumor Cell><Tumor Cell Line><Tumor Immunity><Tumor Necrosis Factor Receptor Superfamily Member 5 Gene><Tumor Tissue><Tumor-Associated Antigen><Unresectable><Vaccinated><Viral><X-Radiation><X-Ray Radiation><X-Ray Therapy><X-ray><Xray><Xray Therapy><aPD-1><aPD1><absorption><activate T cells><adaptive immunity><anti programmed cell death 1><anti-PD-1><anti-PD-1 Ab><anti-PD-1 antibodies><anti-PD-1 monoclonal antibodies><anti-PD1><anti-PD1 Ab><anti-PD1 antibodies><anti-PD1 monoclonal antibodies><anti-programmed cell death protein 1><anti-programmed cell death protein 1 antibodies><anti-programmed death-1 antibody><anti-tumor immunity><antiPD-1><antiPD1><antigen processing><antitumor immunity><biologic><biological signal transduction><cancer antigens><cancer immunity><cancer metastasis><cancer microenvironment><chemo-/radio-therapy><chemo-radio-therapy><chemo-radiotherapy><chemoradiation><chemoradiation therapy><chemoradiation treatment><chemoradiotherapy><clinical efficacy><clinical relevance><clinically relevant><combination therapy><combinatorial immunotherapy><combined modality treatment><combined treatment><compare effectiveness><design><designing><dosimetry><dual immunotherapy><epigenetic gene silencing><epigenetic silencing><epigenetically><exhaust><fighting><fire><genetically engineered mouse model><genetically engineered murine model><host response><immune competent><immune drugs><immune evasive><immune microenvironment><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapeutics><immune-based therapies><immune-based treatments><immuno therapy><immunodeficient mouse model><immunogenic><immunologic reactivity control><immunologic therapeutics><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive microenvironment><immunosuppressive response><immunosuppressive tumor microenvironment><immunotherapeutics><immunotherapy agent><improved><in vivo><indexing><inhibitor><interest><ionization><irradiation><kinetic model><light intervention><light treatment><malignancy><member><mouse model><multi-modal therapy><multi-modal treatment><murine model><neoplasm/cancer><neoplastic cell><p50><pancreas radiation therapy><pancreas radiotherapy><pancreatic cancer cells><pancreatic cancer model><pancreatic cancer patients><pancreatic malignancy><pancreatic neoplasia><pancreatic neoplasm><pancreatic tumor cells><pancreatic tumor model><particle><particle beam><patients with pancreatic cancer><predict therapeutic response><predict therapy response><prognostic of overall survival><prognostic of survival><programmed cell death 1><programmed cell death protein 1><programmed death 1><programs><proton therapy><radiation treatment><radio-chemo-therapy><radio-chemotherapy><radiochemotherapy><randomized trial><repair><repaired><response><sle2><social role><standard of care><success><survival prognosis><systemic lupus erythematosus susceptibility 2><therapy prediction><thymus derived lymphocyte><treatment prediction><treatment response prediction><treatment with radiation><tumor><tumor cell metastasis><tumor immune microenvironment><tumor microenvironment><tumor xenograft><tumor-immune system interactions><tumor-specific antigen><αPD-1><αPD1>