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Principal Investigator: Tayyaba Hasan
Organization: MASSACHUSETTS GENERAL HOSPITAL
Fiscal Year: 2024
Award: $1,002,287
Funding agency: National Cancer Institute
OVERALL PROGRAM SUMMARY
For optimal cancer therapy, combination approaches that are mechanistically complementary and directed
at non-overlapping molecular targets are needed. Strategically, combinations should be selected such that
the first treatment primes the tumor for the second treatment. Building upon our own findings and work on
photodynamic therapy (PDT) in pancreatic adenocarcinoma (PDAC) and nonmelanoma skin cancer (NMSC),
along with recent advances in immunotherapy, we hypothesize that the damage-related processes triggered
by PDT can form the basis for Photodynamic Priming (PDP) to promote an immune-based combination
therapy. PDP induces immunogenic cell death, enhances influx of tumor infiltrating lymphocytes (TILs), and
sensitizes the tumor microenvironment to immune checkpoint inhibition (ICI). We will capture the PDP effect
to design a non-empiric approach for PDT-ICI combination therapy. We will be helped in this effort by our
recent innovation of hyperspectral confocal imaging that can monitor 6 biomarkers simultaneously in live
tumor bearing animals, and allow quantification of TIL subsets along with PD1/PD-L1 expression changes.
We posit that ICI will be most beneficial when immunologically “cold” tumors can first be converted to “hot”
tumors via PDP treatment, thereby minimizing the ICI dose required and reducing toxicity. Our Program has 3
Research Projects and 2 scientific Cores, plus an Administrative Core. Projects 1 and 2 are largely clinical
while Project 3 is exclusively pre-clinical, driving fundamental findings that form the basis of the hypothesis.
Project 1 introduces a double-priming strategy for the treatment of NMSC; the tumor is first treated pharmaco-
logically with 5-fluorouracil or Vitamin D to enhance PDT priming, which in turn increases the efficacy of ICI.
Project 2 focuses on PDP in pancreatic cancer patients who are unresponsive to chemotherapy. PDT is
delivered under endoscopic ultrasound (EUS) guidance, and timing of ICI delivery is informed by findings from
Project 3 and by examining subpopulations of TILs in metastatic lymph nodes in some patients. Project 3
looks in-depth at PDP induction of TILs in a PDAC murine model, and in patient-derived immune organoids
(PDIO’s). Cores are critical. Core B will assist Projects 1 and 3 with high resolution imaging in preclinical
models and PDIOs, and Core C will support all projects with dosimetry techniques to monitor tumor treatment
response, including radiomics to garner new information from CT scans in PDAC patients. We
propose t h a t new combinations o f PDT with immune checkpoint inhibition (ICI), if done in a rational way
that is informed by optical imaging to monitor molecular responses at the cellular level and in real time, will
reduce a major barrier to ICI therapy (the lack of effective immune cell infiltration into the tumor). Impact and
Relevance: This program positively impacts the treatment of two cancers, PDAC and NMSC, at opposite
ends of the spectrum of high mortality/morbidity and high incidence. Both cancers inflict a heavy societal
burden of cost and suffering. Findings from this work could also be translatable to other types of cancer.
Terms: <5-FU><5-Fluracil><5FU><Abscission><Acceleration><Animals><Automobile Driving><BPD verteporfin><BPD-MA><Behavior><Benzoporphyrin Derivative Monoacid Ring A><Biological Markers><Budgets><CAT scan><CT X Ray><CT Xray><CT imaging><CT scan><Cancer Treatment><Cancers><Categories><Checkpoint inhibitor><Clinical><Clinical Research><Clinical Study><Clinical Trials><Collaborations><Combined Modality Therapy><Computed Tomography><Development><Diagnostic><Disease><Disorder><Dose><Economic Burden><Eligibility><Eligibility Determination><Endoscopic Ultrasonography><Endoscopy><Environment><Excision><Exocrine Pancreas Carcinoma><Extirpation><Fibroblasts><Fluoro Uracil><Fluorouracil><Fluoruracil><Fluouracil><Future><General Radiology><Human><Image><Imaging Device><Imaging Instrument><Imaging Tool><Immune><Immune Monitoring><Immune checkpoint inhibitor><Immune infiltrates><Immune mediated therapy><Immune response><Immunes><Immunochemical Immunologic><Immunocompetent><Immunologic><Immunologic Monitoring><Immunological><Immunological Monitoring><Immunological response><Immunologically><Immunologically Directed Therapy><Immunologics><Immunomodulation><Immunomonitoring><Immunotherapy><Incidence><Industry><Infiltration><Keratinocyte carcinoma><Keytruda><Knowledge><Learning><Lesion><Literature><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><Lymphocyte Subpopulations><Lymphocyte Subset><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Skin Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Mediating><Mice><Mice Mammals><Microsatellite Instability><Modeling><Modern Man><Molecular><Molecular Target><Monitor><Morbidity><Morbidity - disease rate><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Non-Melanoma Skin Cancer><Optics><Organoids><Outcome><P01 Mechanism><P01 Program><PD 1><PD-1><PD-1/PD-L1><PD-1/PDL1><PD1><PD1-PD-L1><PD1/PD-L1><PD1/PDL1><PUVA><PUVA Photochemotherapy><Pancreas Adenocarcinoma><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreatic Adenocarcinoma><Pancreatic Cancer><Pancreatic Ductal Adenocarcinoma><Pancreatic carcinoma><Pathway interactions><Patients><Pattern><Peer Review><Permeability><Photochemotherapy><Photodynamic Therapy><Pre-Clinical Model><Preclinical Models><Process><Prognosis><Program Project Grant><Program Research Project Grants><Proteins><Protocol Screening><Publications><R-Series Research Projects><R01 Mechanism><R01 Program><Radiology><Radiology Specialty><Regimen><Removal><Research><Research Grants><Research Program Projects><Research Project Grants><Research Projects><Scientific Publication><Skin Cancer><Skin Carcinoma><Surgical Removal><T-Cell Activation><T-Cell Subsets><T-Lymphocyte Subsets><Techniques><Therapeutic><Time><Tomodensitometry><Toxic effect><Toxicities><Tumor Escape><Tumor Immune Escape><Tumor-Infiltrating Lymphocytes><United States><VIT D><Verteporfin><Visible Light><Visible Light Radiation><Visible Radiation><Visudyne><Vitamin D><Work><X-Ray CAT Scan><X-Ray Computed Tomography><X-Ray Computerized Tomography><Xray CAT scan><Xray Computed Tomography><Xray computerized tomography><aPD-1><aPD1><activate T cells><anti programmed cell death 1><anti-PD-1><anti-PD1><anti-cancer therapy><anti-programmed cell death protein 1><antiPD-1><antiPD1><benzoporphyrin D><bio-markers><biologic marker><biomarker><cancer evasion><cancer immune escape><cancer immune evasion><cancer microenvironment><cancer therapy><cancer type><cancer-directed therapy><catscan><check point inhibition><checkpoint inhibition><chemotherapy><clinical translation><clinically translatable><cohort><combination therapy><combined modality treatment><combined treatment><computed axial tomography><computer tomography><computerized axial tomography><computerized tomography><conference><confocal imaging><convention><conventional therapy><conventional treatment><cost><cytotoxic><design><designing><developmental><dosimetry><driving><endoscopic imaging><endoscopic ultrasound><high resolution imaging><host response><image guidance><image guided><imaging><immune cell infiltrate><immune check point><immune check point inhibition><immune check point inhibitor><immune checkpoint><immune checkpoint inhibition><immune competent><immune modulation><immune regulation><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immunecheckpoint><immuno therapy><immunogenic apoptosis><immunogenic cell death><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><improved><innovate><innovation><innovative><lymph gland><lymph nodes><lymphnodes><malignancy><malignant skin tumor><mortality><mouse model><multi-modal therapy><multi-modal treatment><murine model><neoplasm/cancer><neoplasm/cancer photoradiation therapy><non-contrast CT><noncontrast CT><noncontrast computed tomography><nonmelanoma skin cancer><novel><optic imaging><optical><optical imaging><pancreas carcinoma><pancreatic cancer model><pancreatic cancer patients><pancreatic malignancy><pancreatic tumor model><pathway><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><patients with pancreatic cancer><pembrolizumab><pharmacologic><pre-clinical><pre-clinical study><preclinical><preclinical study><programmed cell death 1><programmed cell death protein 1><programmed death 1><programs><radiomics><recruit><resection><response><response to therapy><response to treatment><side effect><sle2><success><summit><symposia><symposium><systemic lupus erythematosus susceptibility 2><therapeutic response><therapy response><tool><treatment response><treatment responsiveness><treatment strategy><tumor><tumor evasion><tumor immune evasion><tumor microenvironment><ultrasound><verteporphin><αPD-1><αPD1>