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Principal Investigator: Wen Jiang
Organization: UNIVERSITY OF TX MD ANDERSON CAN CTR
Fiscal Year: 2024
Award: $539,426
Funding agency: National Cancer Institute
PROJECT SUMMARY
Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of hematologic
cancers. However, for solid tumors, CAR T cells face challenges including intratumor heterogeneity, dynamic
expression of target receptors, and often the inability for T cells to traffic to tumors to mediate the desired
antitumor effect. In contrast to the lack of T cell infiltrates, many solid tumors are abundant in immune
suppressive myeloid cells including macrophages. Therefore, converting these immune suppressive cells into
tumoricidal phenotype represents a promising strategy for cell-based therapy. There are now strong interest in
generating CAR macrophages in which autologous macrophages are transduced with CAR delivered by viral
vectors ex vivo to enhance their phagocytosis, antigen presentation and cytokine producing capabilities
following re-infusion. However, ex vivo preparation of CAR macrophages is complex, time consuming, and due
to the non-dividing nature of macrophages, is often inefficient. With the recent advances in mRNA-based
therapeutics, it is now possible to reprogram specific immune cell populations in vivo, thus eliminating the
complex ex vivo production of autologous CAR cells. Our present proposal aims to propose an innovative
strategy of generating CAR macrophages in vivo using mRNA-loaded exosomes to treat HER2 receptor
positive breast cancer. This will be the first study to evaluate the feasibility of producing CAR macrophages in
vivo using mRNA delivery platforms and assessing the antitumor efficacy of CAR macrophages for cancer
immunotherapy. We hypothesize that our strategy represents a revolutionary way to produce CAR
macrophages in vivo using CAR mRNA-loaded exosome and offers a promising new approach for cell therapy
against solid tumors. Our previous study showed that we can efficiently produce mRNA-loaded exosomes to
restore protein expression in solid tumors. Furthermore, our preliminary experiments showed that the
exosomes loaded with HER2 CAR mRNA can produce CAR macrophages in vivo with enhanced effector
functions. Our current study will test our overall hypothesis by using the following specific aims. In Aim 1, we
will evaluate the dynamics and toxicity of CAR macrophage production in vivo using CAR mRNA exosomes. In
Aim 2, we will evaluate transcriptomic and functional profiles of in vivo generated CAR macrophages, Finally,
in Aim 3, we will assess the antitumor effect of in vivo generated CAR macrophages against both murine and
human HER2 expressing breast cancer. If successful, our proposed research can overcome a major technical
hurdle that is currently facing cell therapy. The mRNA exosome platform could potentially be expanded to other
CAR constructs and greatly expand the potential utility of cell therapy for breast and other solid cancers.
Terms: <Animals><Antibodies><Antigen Presentation><Antitumor Response><Autologous><Breast><Breast Cancer><Breast Cancer Cell><Breast Cancer Model><Breast tumor model><CAR T cell therapy><CAR T cells><CAR T therapy><CAR modified T cells><CAR-T><CAR-Ts><CD11b><CD8><CD8B><CD8B1><CD8B1 gene><CR3A><Cancers><Cell Body><Cell Therapy><Cells><Clinical><Complex><Consumption><Dose><EGF Receptor><EGFR><ERBB Protein><Engineering><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Exhibits><Face><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Gene Expression><Generations><Genes><HER1><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic Cancer><Human><ITGAM><ITGAM gene><Immune><Immune Cell Activation><Immunes><Immunocompetent><Immunofluorescence><Immunofluorescence Immunologic><Immunologic Stimulation><Immunological Stimulation><Immunostimulation><In Vitro><Infusion><Infusion procedures><Intratumoral heterogeneity><LYT3><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><MAC1A><MO1A><Macrophage><Malignant Breast Neoplasm><Malignant Hematologic Neoplasm><Malignant Neoplasms><Malignant Tumor><Maps><Mediating><Membrane><Messenger RNA><Metastatic breast cancer><Mice><Mice Mammals><Modern Man><Murine><Mus><Myeloid-derived suppressor cells><Mφ><Nature><PDX model><Pathway interactions><Patient derived xenograft><Phagocytes><Phagocytic Cell><Phagocytosis><Phenotype><Population><Pre-Clinical Model><Preclinical Models><Preparation><Production><RNA Seq><RNA sequencing><RNAseq><Receptor Cell><Receptor Protein><Regimen><Research><Solid><Solid Neoplasm><Solid Tumor><Spatial Distribution><Specificity><T cell infiltration><T cells for CAR><T-Cells><T-Lymphocyte><TGF-alpha Receptor><Testing><Therapeutic><Time><Toxic effect><Toxicities><Transforming Growth Factor alpha Receptor><Urogastrone Receptor><Viral Vector><amebocyte><anti-cancer immunotherapy><anti-tumor effect><anti-tumor response><anticancer immunotherapy><antigen-specific T cells><antitumor effect><breast tumor cell><c-erbB-1><c-erbB-1 Protein><cancer immunotherapy><cancer microenvironment><cell mediated therapies><cell-based therapeutic><cell-based therapy><cellular therapeutic><cellular therapy><chimeric antigen T cell receptor><chimeric antigen receptor><chimeric antigen receptor (CAR) T cell therapy><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cell therapy><chimeric antigen receptor T cells><chimeric antigen receptor T therapy><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><cytokine><deliver mRNA><deliver messenger RNA><delivery system for mRNA><design><designing><draining lymph node><engineered exosomes><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><exosome><experiment><experimental research><experimental study><experiments><extracellular><faces><facial><flow cytophotometry><heterogeneity in tumors><immune activation><immune competent><immune-based cancer therapies><immunosuppressive myeloid cells><immunotherapy for cancer><immunotherapy of cancer><in vivo><infusions><innovate><innovation><innovative><insight><interest><intra-tumoral heterogeneity><intratumor heterogeneity><lymph gland><lymph nodes><lymphnodes><mRNA><mRNA delivery><malignancy><malignant breast tumor><mammary cancer model><mammary tumor model><membrane structure><messenger RNA delivery><multiphoton excitation microscopy><multiphoton microscopy><myeloid suppressor cells><myeloid-derived suppressive cells><neoplasm/cancer><new approaches><novel approaches><novel strategies><novel strategy><pathway><patient derived xenograft model><preparations><programs><protein expression><proto-oncogene protein c-erbB-1><receptor><reconstitute><reconstitution><regional lymph node><suppressive myeloid cells><thymus derived lymphocyte><transcriptome sequencing><transcriptomic sequencing><transcriptomics><tumor><tumor growth><tumor heterogeneity><tumor microenvironment>