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Principal Investigator: Pawel Kalinski
Organization: ROSWELL PARK CANCER INSTITUTE CORP
Fiscal Year: 2024
Award: $1,494,670
Funding agency: National Cancer Institute
The revised P01CA234212 tests novel strategies to promote selective CTL entry into tumor micro-
environments (TME) and sensitize “cold” tumors to immunotherapy. Our preclinical and early clinical data
demonstrate that the chemokine-modulating (CKM) regimen targeting toll-like receptor-3 (TLR3), type-1
interferons (IFN) and the PGE2 system, selectively enhances CTL numbers but reduces regulatory T(reg) cells
in TME, uniformly sensitizing tumors for the therapeutic effectiveness of PD-1 blockers and specialized
dendritic cell vaccines (αDC1) in melanoma, colorectal cancer (CRC) and ovarian cancer (OvCa). We will now:
1) Determine local immunologic efficacy of systemically- or locally applied CKMs in cancer patients; 2) Identify
the most effective ways of using CKM to enhance antitumor effects DC therapies and PD-1 blockade; and 3)
Evaluate the clinical activity of the resulting therapies in PD-1-resistant cancer patients, and identify the most
relevant TME correlates of clinical benefit.
Project 1 Combinatorial adjuvants promote uniform and selective intratumoral CTL infiltration will test
in a Phase IIa trial NCT03403634 whether systemic administration of CKM composed of rintatolimod (TLR3-
ligand) IFNα and celecoxib promotes local CTL accumulation in TME of metastatic colorectal cancer (CRC).
Magnitude of effects, tumor-selectivity (vs surrounding tissues) and mouse studies will guide the design of the
second trial which will evaluate the clinical efficacy of sequential CMK/anti-PD-1 application in CRC patients.
Project 2 Local immunotherapy corrects chemokine patterns in OvCa will complete the phase II portion of
trial NCT02432378 to test the specificity of local CKM in attracting CTLs (rather than Tregs) to the TME of
OvCa patients vaccinated with αDC1 loaded with own tumor cells (αDC1[tumor]) and identify “secondary”
mechanisms or treatment resistance. The results will inform preclinical studies and the design of the second
trial to determine the clinical activity of sequential treatment with DC[tumor]/CKM followed with PD-1 blockade.
Project 3 Chemokine modulation to enhance CD8+ TIL recruitment and cross-priming in the TME is
based on our latest observations (NCT01876212) of 57% objective response rate (ORR) to αDC1 vaccine
targeting tumor blood vessels (αDC1[TBVA] in the 4 of 7 melanoma patients with primary PD1 resistance and
46% objective clinical benefit overall (6/13 patients). We will now perform phase II trial to evaluate the clinical
activity of αDC1[DBVA] combined with systemic CKM (BB-IND16,704) in stage IV melanoma patients with
primary PD1 resistance. Using correlative studies and mouse in vivo models, we will develop optimized and
potentially simplified vaccines to complement CKM and PD-1 blockade for durable therapeutic benefit.
Impact: We will test widely-applicable complementary approaches to promote selective entry of therapeutic
CTLs into tumors. Since intratumoral CTL numbers predict survival and therapeutic advantage of checkpoint
blockers in multiple cancer types, the results are likely to benefit a broad range of cancer patients.
Terms: <(IFN) α><(IFN)-α><(IFN)α><(TNF)-α><Adjuvant><Affect><Alferon><Antigens><Autologous><Biological Markers><Blood><Blood Reticuloendothelial System><Blood Vessel Tumor><Body Tissues><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><Cachectin><Cancer Patient><Cancers><Cell Body><Cell Count><Cell Function><Cell Number><Cell Physiology><Cell Process><Cell-Mediated Lympholytic Cells><Cells><Cellular Function><Cellular Physiology><Cellular Process><Chemokine Receptor Gene><Chemotactic Cytokines><Clinical><Clinical Data><Clinical effectiveness><Cohort Studies><Colorectal Cancer><Combined Modality Therapy><Complement><Complement Proteins><Concurrent Studies><Correlative Study><Cross-Priming><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Cytotoxic cell><Data><Dendritic Cell Vaccine><Development><Dinoprostone><Disease><Disorder><Ectopic lymphoid organ><Ectopic lymphoid structure><Effectiveness><Effector Cell><Future><Goals><Homologous Chemotactic Cytokines><IFN><IFN Alpha><IFN α><IFN-α><IFNa><IFNα><Immune><Immune mediated therapy><Immune system><Immunes><Immunochemical Immunologic><Immunologic><Immunologic Tests><Immunological><Immunological Tests><Immunologically><Immunologically Directed Therapy><Immunologics><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><Inpatients><Intercrines><Interferon Alfa-n3><Interferon alpha><Interferon-α><Interferons><K Cells><K lymphocyte><Killer Cells><LYT3><Lesion><Leukocyte Interferon><Ligands><Link><Liver><Lymphoblast Interferon><Lymphoblastoid Interferon><Macrophage-Derived TNF><Malignant Melanoma><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Tumor><Malignant Tumor of the Ovary><Malignant neoplasm of ovary><Melanoma><Melanoma patient><Mice><Mice Mammals><Microsatellite Markers><Microsatellite Repeats><Microsatellites><Monocyte-Derived TNF><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Myeloid-derived suppressor cells><NK Cells><Natural Killer Cells><Neoplasms in Vascular Tissue><Ovary Cancer><P01 Mechanism><P01 Program><PD 1><PD-1><PD-1 blockade><PD-1/PD-L1><PD-1/PDL1><PD1><PD1 blockade><PD1-PD-L1><PD1/PD-L1><PD1/PDL1><PGE2><PGE2 alpha><PGE2alpha><Patients><Pattern><Peptide Vaccines><Peptides><Phase><Prediction of Response to Therapy><Productivity><Program Project Grant><Program Research Project Grants><Prostaglandin E2><Prostaglandin E2 alpha><Prostaglandin E2alpha><Prostaglandins><Prostanoids><Refractory><Regimen><Regulatory T-Lymphocyte><Research Program Projects><Resistance><SIS cytokines><Safety><Sequential Treatment><Solid Neoplasm><Solid Tumor><Specificity><Standardization><Subcellular Process><System><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell infiltration><T cell targeted therapeutics><T cell therapy><T-cell therapeutics><T-cell transfer therapy><T8 Cells><T8 Lymphocytes><TLR3><TLR3 gene><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Tertiary lymphoid structure><Testing><Th-1 Cell><Th1 Cells><Therapeutic><Therapeutic Effect><Tissues><Toll-Like Receptor 3><Treatment Efficacy><Treg><Tumor Cell><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Type 1 Helper Cell><Vaccination><Vaccinee><Vaccines><Vascular Neoplasms><Vascular Tissue Tumor><Vascular Tumor><aPD-1><aPD1><adoptive T cell transfer><adoptive T-cell therapy><anti programmed cell death 1><anti-PD-1><anti-PD-1 blockade><anti-PD1><anti-PD1 blockade><anti-programmed cell death protein 1><anti-tumor effect><antiPD-1><antiPD1><antitumor effect><bio-markers><biologic marker><biomarker><blood vessel neoplasm><cancer microenvironment><cancer type><celebrex><celecoxib><check point blockade><check point blocker><check point inhibition><checkpoint blockade><checkpoint blockers><checkpoint inhibition><chemoattractant cytokine><chemokine><chemokine receptor><clinical efficacy><colon cancer patients><colorectal cancer patients><combination therapy><combinatorial><combined modality treatment><combined treatment><complementation><design><designing><developmental><hepatic body system><hepatic organ system><immune check point blockade><immune check point blocker><immune check point inhibition><immune checkpoint blockade><immune checkpoint blockers><immune checkpoint inhibition><immune clearance><immune elimination><immune suppression><immune suppressive activity><immune suppressive function><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunosuppressive activity><immunosuppressive function><immunosuppressive myeloid cells><immunosuppressive response><improved><in situ vaccine><in vivo Model><intervention efficacy><killer T cell><malignancy><metastatic colo-rectal><metastatic colo-rectal cancer><metastatic colo-rectal carcinoma><metastatic colon cancer><metastatic colorectal><metastatic colorectal cancer><metastatic colorectal carcinoma><multi-modal therapy><multi-modal treatment><myeloid suppressor cells><myeloid-derived suppressive cells><neoplasm/cancer><neoplastic cell><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><objective response rate><ovarian cancer><phase 1 trial><phase 2 trial><phase I trial><phase II trial><pre-clinical><pre-clinical study><preclinical><preclinical study><predict therapeutic response><predict therapy response><programmed cell death 1><programmed cell death protein 1><programmed death 1><programs><prospective><recruit><refractory cancer><regulatory T-cells><resistance to therapy><resistant><resistant cancer><resistant to therapy><response><sle2><suppressive myeloid cells><survival prediction><systemic lupus erythematosus susceptibility 2><tertiary lymphoid organ><therapeutic T-cell platform><therapeutic effectiveness><therapeutic efficacy><therapeutic resistance><therapeutic vaccine><therapy efficacy><therapy optimization><therapy prediction><therapy resistant><tool><translational study><treatment optimization><treatment prediction><treatment resistance><treatment response prediction><treatment vaccines><tumor><tumor microenvironment><vaccinated individual><vaccinated participant><vaccinated patient><vaccinated person><vaccinated subject><vaccine for the treatment><vaccine for treatment><αPD-1><αPD1>