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Principal Investigator: Joshua D Brody
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2024
Award: $368,346
Funding agency: National Cancer Institute
PROJECT SUMMARY: Checkpoint blockade has had tremendous impact on cancer therapy, but only
a subset of patients respond. While non-response may be due to lack of tumor-associated antigen
(TAA), our group and others have shown that –as important as having TAA– is the immune system’s
capacity to present TAA on antigen presenting cells, specifically a subset of ‘cross-presenting’ Batf3-
expressing dendritic cells (DC). Without Batf3-DC, anti-tumor effects of PD1 blockade are lost.
Therefore we hypothesize that increasing cross-priming DC will improve the efficacy of PD1 blockade.
To increase cross-priming, we developed an in situ vaccination (ISV) combining (i) Flt3L, to recruit
DC (ii) radiotherapy (XRT) to load DC with TAA, and (iii) a TLR agonist to activate the TAA-loaded DCs.
We tested this novel ISV (Flt3L/XRT/polyIC) in advanced stage lymphoma patients and observed
dramatic systemic remissions in some patients. To improve the ISV, we developed a murine ISV model
which recapitulated the clinical findings and also increased cure rates of PD1 blockade from 0% to
~75%, which prompted a new trial, using ISV plus pembrolizumab, opened in 02/19.
Still, the unmet clinical need is great, to understand and improve upon our ISV and PD1 blockade,
we will develop methods to measure cross-priming, using sophisticated mouse models (Aim 1) and
deep immune monitoring of patient samples from the two trials (Aim 2,3).
In Aim 1, we will determine how ISV enhances PD1 blockade in mouse models in which we preserve
only cross-priming or only direct-priming (by the tumor) or both. Specifically, we will: (a) determine if
cross-priming is necessary for ISV anti-tumor effects (b) define a signature of cross-primed T cells,
including their expression of checkpoint molecules, and (c) characterize resistance mechanisms.
In Aim 2, we will demonstrate that ISV cross-primes patients’ tumor-reactive T cells by analyzing
banked samples from our ISV-treated patients. Specifically, we will: (a) use ex vivo autologous tumor:T
cell co-cultures, flow-sorting, and immunoSEQ to identify anti-tumor T cells, and (b) use 5’ scRNAseq/
TCRseq to quantify and characterize those T cells and then correlate them with clinical responses.
In Aim 3, we will analyze banked samples from our ongoing ISV plus pembrolizumab trial which also
includes administration of a surrogate Ag at the ISV site. Specifically, we will: (a) assess whether
surrogate Ag cross-presentation is improved by ISV and PD1 blockade and whether it predicts clinical
outcomes, and (b) determine mechanisms of tumoral suppression of cross-priming.
Lymphomas kill ~21,000 patients annually in the U.S. The most common lymphomas are incurable
with standard therapies and minimally responsive to checkpoint blockade. Improving our understanding
of ISV and PD1 blockade will improve their efficacy, and thereby improve the lives of our patients.
Terms: <Agonist><Animal Model><Animal Models and Related Studies><Antigen-Presenting Cells><Au antigen><Australia Antigen><Autologous><B7-H1><B7H1><Blood><Blood Reticuloendothelial System><CD274><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CRM-197><CRM197><Cancer Treatment><Cell Function><Cell Physiology><Cell Process><Cellular Function><Cellular Physiology><Cellular Process><Chemotactic Cytokines><Clinical><Clone Cells><Co-culture><Cocultivation><Coculture><Coculture Techniques><Cross Presentation><Cross-Priming><Dendritic Cells><Disease remission><Distant><FLT 3 Ligand><FLT3 ligand><FLT3L><FLT3LG><FLT3LG gene><FMS-Related Tyrosine Kinase 3 Ligand Gene><FMS-Related Tyrosine Kinase-3 Ligand><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Germinoblastic Sarcoma><Germinoblastoma><Goals><HBsAg><HBsAg (hepatitis B surface antigen)><Hepatitis B Surface Antigens><Hodgkin Disease><Hodgkin Disorder><Hodgkin lymphoma><Hodgkin's><Hodgkin's Lymphoma><Hodgkin's disease><Hodgkins lymphoma><Homologous Chemotactic Cytokines><Immune Monitoring><Immune mediated therapy><Immune system><Immunologic Monitoring><Immunological Monitoring><Immunologically Directed Therapy><Immunology><Immunomonitoring><Immunotherapy><Indolent><Infiltration><Intercrines><Keytruda><Knowledge><Lymphoma><Malignant Lymphogranuloma><Malignant Lymphoma><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Measures><Mediating><Methods><Mice><Mice Mammals><Minority><Modeling><Molecular><Molecular Tumor Suppression><Murine><Mus><Mutation><NHL patients><Non-Hodgkin's Lymphoma><Nonhodgkins Lymphoma><Oncology><Oncology Cancer><Outcome><PD 1><PD-1><PD-1 antibody therapy><PD-1 blockade><PD-1 therapy><PD-L1><PD1><PD1 antibody therapy><PD1 based treatment><PD1 blockade><PDL-1><PDL1><Patient Monitoring><Patients><Phenotype><Pre-Clinical Model><Preclinical Models><Production><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Radiation therapy><Radiotherapeutics><Radiotherapy><Remission><Resistance><Reticulolymphosarcoma><SIS cytokines><STK1-ligand><Sampling><Site><Sorting><Subcellular Process><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell receptor repertoire sequencing><T cell receptor sequencing><T cell response><T cell targeted therapeutics><T cell therapy><T-Cell Activation><T-Cells><T-Lymphocyte><T-cell therapeutics><T-cell transfer therapy><T8 Cells><T8 Lymphocytes><TCR repertoire sequencing><TCR sequencing><TCR-seq><TCRseq><Techniques><Testing><Therapeutic Effect><Tumor Antigens><Tumor Suppression><Tumor-Associated Antigen><Veiled Cells><Work><aPD-1><aPD-1 therapy><aPD-1 treatment><aPD1><aPD1 therapy><aPD1 treatment><accessory cell><activate T cells><adoptive T cell transfer><adoptive T-cell therapy><anti programmed cell death 1><anti-PD-1><anti-PD-1 blockade><anti-PD-1 therapy><anti-PD-1 treatment><anti-PD1><anti-PD1 blockade><anti-PD1 therapy><anti-PD1 treatment><anti-cancer therapy><anti-programmed cell death 1 therapy><anti-programmed cell death protein 1><anti-programmed cell death protein 1 therapy><anti-tumor effect><antiPD-1><antiPD1><antigen-specific T cells><antitumor effect><cancer antigens><cancer microenvironment><cancer therapy><cancer-directed therapy><check point blockade><checkpoint blockade><chemoattractant cytokine><chemokine><clinical remission><cross reacting material 197><cytokine><flk2 ligand><flk2-flt3 ligand><flt3 ligand protein><genome mutation><hepatitis associated antigen><immune check point blockade><immune checkpoint blockade><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><improved><in situ anti-tumor vaccination><in situ antitumor vaccination><in situ cancer vaccination><in situ tumor vaccination><in situ vaccination><insight><model of animal><mouse model><murine model><non-Hodgkin's lymphoma patients><non-Hodgkins disease><nonHodgkin's lymphoma patients><novel><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><pembrolizumab><predict clinical outcome><preservation><prevent><preventing><programmed cell death 1><programmed cell death ligand 1><programmed cell death protein 1><programmed cell death protein 1 therapy><programmed cell death protein ligand 1><programmed death 1><protein death-ligand 1><radiation treatment><recruit><resistance mechanism><resistant><resistant mechanism><response><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><sle2><stem cell tyrosine kinase 1 ligand><systemic lupus erythematosus susceptibility 2><therapeutic T-cell platform><thymus derived lymphocyte><treatment with radiation><tumor><tumor microenvironment><tumor-specific antigen><usability><αPD-1><αPD1>