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Principal Investigator: Anusha Kalbasi
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $228,439
Funding agency: National Cancer Institute
PROJECT SUMMARY
Despite chemotherapy, radiation and surgery, patients with undifferentiated pleomorphic sarcoma (UPS)
frequently suffer incurable disease relapse. Immune checkpoint blockade is a promising new therapeutic
approach for patients with UPS which promotes T cell mediated anti-tumor immunity. Still, the majority of
patients do not benefit. Radiation therapy (RT), a cornerstone of preoperative treatment of UPS, can instigate
T cell anti-tumor responses and synergize with immune checkpoint blockade. But RT can also result in the
recruitment of immunosuppressive, pro-tumor myeloid cells that restrain anti-tumor T cell responses. This is
particularly relevant in UPS, which is characterized by a brisk myeloid cell infiltrate. The candidate
hypothesizes that reprogramming RT-induced myeloid cells toward an antigen-presenting, pro-inflammatory
phenotype will promote T cell mediated anti-tumor immunity in UPS.
To investigate the hypothesis the candidate proposes studies using BO-112, a synthetic nanoplexed version of
poly I:C that activates double-stranded RNA sensing pathways, which are highly active in myeloid cells. These
studies will be conducted in murine models of UPS (Aim 1) as well as in UPS patients (Aim 2). In Aim 1, the
candidate will determine the impact of BO-112 on the fate, phenotype and immunomodulatory function of RT-
induced myeloid cells. In Aim 2, the candidate evaluates the capacity of BO-112, RT, and anti-PD1 immune
checkpoint blockade to remodel the myeloid compartment and instigate anti-tumor T cell responses in UPS
patients enrolled on a window of opportunity phase 1 clinical trial. These studies will provide key insight into
plasticity of RT-induced myeloid subsets, and their role in T cell mediated anti-tumor immunity, especially in
response to BO-112.
The candidate is an Assistant Professor in Radiation Oncology at UCLA specializing in the treatment of
sarcoma. His scientific track record in tumor immunology and cancer immunotherapy highlights his
commitment to an academic career in this field. The candidate's time is protected for research and career
development (80% effort), and he has the space, equipment, personnel and resources necessary to complete
the proposed studies. Along with his mentor, Dr. Antoni Ribas, and co-mentor, Dr. William McBride, the
candidate has developed a comprehensive career development and training plan that will build expertise in
four areas: (1) myeloid cell biology and plasticity, (2) genetic mouse models as tools to study sarcoma and the
immune system, (3) analysis and interpretation of high-dimensional single cell phenotyping and transcriptomic
data, and (4) conduct of a translational phase 1 clinical trial. These career development activities will support
completion of the proposal and facilitate the transition to an independent scientific career conducting bench-to-
bedside research, with an emphasis on leveraging translational immunology to transform the care of patients
with sarcoma.
Terms: <21+ years old><3-D><3-Dimensional><3D><3D cell culture><3D culture><Abnormal Lymphocyte><Address><Adjuvant Study><Adjuvant Trials><Adopted><Adoptive Transfer><Adult><Adult Human><Antigen Presentation><Antitumor Response><Ants><Area><Atypical lymphocyte><Autologous><B220><Bone Marrow><Bone Marrow Reticuloendothelial System><CD45><Cancers><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular biology><Clinical><Clinical Trials><Co-culture><Cocultivation><Coculture><Coculture Techniques><Combination immunotherapy><Cytometry><Data><Dependence><Development and Research><Distant Cancer><Distant Metastasis><Double-Stranded RNA><Early-Stage Clinical Trials><Equation><Equilibrium><Equipment><Failure><Fibroxanthosarcoma><Foundations><Frequencies><GP180><Genetic><Goals><Human Resources><Immune mediated therapy><Immune system><Immunity><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Immunologically Directed Therapy><Immunomodulation><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><In Vitro><Induction Therapy><Infiltration><Inflammatory><Interferon Type I><Intracellular Communication and Signaling><Investigation><Investigators><KO mice><Knock-out Mice><Knockout Mice><LY5><Literature><Localized Disease><Malignant Fibrous Histiocytoma><Malignant Fibroxanthoma><Malignant Neoplasms><Malignant Soft Tissue Neoplasm><Malignant Tumor><Manpower><Mediating><Mentors><Mice><Mice Mammals><Modeling><Murine><Mus><Myelogenous><Myeloid><Myeloid Cells><NEOADJ><Neoadjuvant><Neoadjuvant Therapy><Neoadjuvant Treatment><Nivolumab><Null Mouse><Opdivo><Operative Procedures><Operative Surgical Procedures><PD 1><PD-1><PD1><PTPRC><PTPRC gene><Pathway interactions><Patient Care><Patient Care Delivery><Patients><Phase><Phase 1 Clinical Trials><Phase I Clinical Trials><Phenotype><Poly I-C><Polyinosinic-Polycytidylic Acid><Population><Productivity><R & D><R&D><Radiation><Radiation Oncology><Radiation therapy><Radiotherapeutics><Radiotherapy><Reactive Lymphocyte><Recurrent disease><Relapsed Disease><Research><Research Personnel><Research Resources><Researchers><Resources><Role><SYS-TX><Sarcoma><Signal Transduction><Signal Transduction Systems><Signaling><Soft tissue sarcoma><Surgical><Surgical Interventions><Surgical Procedure><Systemic Therapy><T cell response><T-Cell Activation><T-Cell Proliferation><T-Cells><T-Lymphocyte><T200><Time><Training><Tumor Immunity><Tumor Promotion><Tumor-Derived><Tumor-Infiltrating Lymphocytes><Undifferentiated><Undifferentiated pleomorphic sarcoma><Virus><aPD-1><aPD1><activate T cells><adjuvant protocol><adulthood><anti programmed cell death 1><anti-PD-1><anti-PD1><anti-cancer immunotherapy><anti-programmed cell death protein 1><anti-tumor immunity><anti-tumor response><antiPD-1><antiPD1><anticancer immunotherapy><antitumor immunity><balance><balance function><bench bed side><bench bedside><bench to bed side><bench to bedside><bench to clinic><bench to clinical practice><biological signal transduction><cancer immunity><cancer immunology><cancer immunotherapy><care for patients><care of patients><career><career development><caring for patients><cell biology><check point blockade><checkpoint blockade><chemotherapy><combinatorial immunotherapy><cytokine><dsRNA><dual immunotherapy><high dimensionality><immune check point blockade><immune checkpoint blockade><immune modulation><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immuno therapy><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunosuppressive activity><immunosuppressive function><immunosuppressive response><immunotherapy for cancer><immunotherapy of cancer><improved><in vitro Assay><induction therapies><insight><irradiation response><malignancy><malignant soft tissue fibrous histiocytoma><malignant soft tissue tumor><mouse model><murine model><nano><neoplasm immunology><neoplasm/cancer><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><older adult><older adulthood><participant enrollment><pathway><patient enrollment><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><personnel><phase I protocol><poly I:C><poly IC><poly(I:C)><professor><programmed cell death 1><programmed cell death protein 1><programmed death 1><programs><radiation response><radiation treatment><recruit><research and development><response><response to radiation><restraint><safety testing><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><sle2><social role><soft tissue><success><surgery><synergism><systemic lupus erythematosus susceptibility 2><three dimensional><three dimensional cell culture><thymus derived lymphocyte><tool><transcriptomics><translational immunology><treatment with radiation><tumor><tumor growth><tumor immunology><αPD-1><αPD1>