Combination antigen sensing engineered T cell for precise recognition and enhanced elimination of solid tumors

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: BIN  LIU
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $632,874
Funding agency: National Cancer Institute

Abstract:
The goal of this proposal is to develop an engineered T cell therapy with potential of translation into human
testing. We will develop a clinically optimized combination antigen sensing prime-and-kill circuit T cell for precise
recognition and enhanced elimination of mesothelioma, a rare disease with poor prognosis. The work is built on
our recent progress in T cell engineering and novel tumor antigen discovery: (1) a prime-and-kill dual antigen
AND-gated circuit with fully human components (dubbed as SNIPR for SyNthetic Intramembrane Proteolysis
Receptors) that facilitate clinical translation. (2) A novel tumor specific cell surface antigen ALPPL2 (aka ALPG)
that is expressed in mesothelioma but not any of the normal human tissues except for the placenta. Paired with
the credentialed mesothelioma antigen mesothelin, the ALPPL2 SNIPR → CAR circuit T cell enables precise
temporal and spatial control of T cell activation at the site of the tumor, minimizes on-target off-tumor toxicity,
reduces tonic signaling and T cell exhaustion, and maintains multifunctional T cell states. The circuit design is
modular and flexible and can be induced to locally deliver additional immune modulatory payloads such as
cytokines to further improve efficacy. In addition, our research has shown that SNIPR → CAR circuit T cells are
capable of effectively targeting antigens that are heterogeneously expressed in tumors, a common pitfall for
therapeutic efficacy. We propose to perform translation-enabling studies: (Aim 1) Optimize antibodies for SNIPR
T cell construction, and develop biomarker for patient stratification. (Aim 2) Engineer and evaluate humanized
clinical grade SNIPR → AND logic T cells in vitro and in vivo. (Aim 3) Evaluate SNIPR-engineered prime-and-
kill circuit T cells in killing tumor with heterogeneous target antigen expression. Successful completion of the
project will enable us to move the SNIPR → CAR circuit T cell to translational development and identify via the
biomarker appropriate mesothelioma patients for clinical testing.

Terms: <Address><Affinity><Alkaline Phosphatase><Antibodies><Antibody Fragments><Antigen Targeting><Antigens><B cell malignancy><B lymphoid malignancy><Bacteriophages><Binding><Biological Markers><Body Tissues><CAR T cell therapy><CAR T cells><CAR T therapy><CAR modified T cells><CAR receptor><CAR-T><CAR-Ts><CD8><CD8B><CD8B1><CD8B1 gene><Cancers><Cell Communication and Signaling><Cell Signaling><Cell Surface Antigens><Cell Therapy><Cell surface><Cells Placenta-Tissue><Clinic><Clinical><Clinical Evaluation><Clinical Testing><Collaborations><Credentialing><DNA Binding Domain><DNA-Binding Protein Motifs><Development><Engineering><Family><Generations><Genes><Goals><Hu-mABs><Human><Immune><Immune response><Immunes><Immunoglobulin Fragments><Immunologic Surface Markers><Immunological Surface Markers><Immunological response><Immunomodulation><In Vitro><Intracellular Communication and Signaling><LYT3><Laboratories><Libraries><Logic><MHC Receptor><Major Histocompatibility Complex Receptor><Malignant Mesothelial Neoplasm><Malignant Mesothelial Tumor><Malignant Neoplasm of the Mesothelium><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Mesothelium><Malignant mesothelioma><Mesothelioma><Modeling><Modern Man><Molecular Interaction><Nature><Normal Placentoma><Normal Tissue><Normal tissue morphology><Orphan Disease><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Phages><Placenta><Placenta Embryonic Tissue><Placentome><Preclinical Testing><Prognosis><Protein Cleavage><Proteolysis><Pure Seminoma><Rare Diseases><Rare Disorder><Receptor Protein><Refractory><Relapse><Reporting><Research><Research Specimen><Sampling><Seminoma><Signal Transduction><Signal Transduction Systems><Signaling><Site><Solid Neoplasm><Solid Tumor><Soluble Mpf/Mesothelin-Related Protein><Specificity><Specimen><Surface Antigens><System><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell targeted therapeutics><T cell therapy><T cells for CAR><T-Cell Activation><T-Cell Antigen Receptors><T-Cell Receptor><T-Cells><T-Lymphocyte><T-cell therapeutics><T-cell transfer therapy><Technology><Testing><Tissues><Toxic effect><Toxicities><Transactivation><Transcription Activation><Transcriptional Activation><Translations><Treatment Efficacy><Tumor Antigens><Tumor Cell><Tumor-Associated Antigen><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Work><Xenograft Model><activate T cells><adoptive T cell transfer><adoptive T-cell therapy><alkaline phosphomonoesterase><antibody engineering><antigen binding><antigen bound><bacterial virus><bio-markers><biologic marker><biological signal transduction><biomarker><cancer antigens><cancer microenvironment><cell mediated therapies><cell-based therapeutic><cell-based therapy><cellular therapeutic><cellular therapy><chimeric antigen T cell 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><clinical efficacy><clinical test><clinical translation><clinically translatable><coxsackie-adenovirus receptor><cytokine><design><designing><developmental><engineered T cells><exhaustion><extracellular><flexibility><flexible><genetically engineered T-cells><glycerophosphatase><host response><humAbs><human DNA><human mAbs><human monoclonal antibodies><human monoclonals><human tissue><immune modulation><immune regulation><immune system response><immunogen><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><improved><in vivo><intervention efficacy><malignancy><member><mesothelin><mesothelioma cancer><neoplasm/cancer><neoplastic cell><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><notch><notch protein><notch receptors><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><orphan disorder><patient biomarkers><patient oriented outcomes><patient stratification><placental trophoblasts><pre-clinical testing><receptor><research clinical testing><stratified patient><success><synthetic antibodies><therapeutic T-cell platform><therapeutic agent development><therapeutic development><therapeutic efficacy><therapy efficacy><thymus derived lymphocyte><trans-activation><transgenic T- cells><translation><translational opportunities><translational potential><tumor><tumor microenvironment><tumor-specific antigen><virus protein><xenograft transplant model><xenotransplant model><yeast protein>