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Principal Investigator: Ravi Bhasker Patel
Organization: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
Fiscal Year: 2024
Award: $580,985
Funding agency: National Cancer Institute
Project Summary & Abstract
Adoptive T cell therapies (ACT) including chimeric antigen receptor (CAR) T cells are novel immunotherapies
with unparalleled successes, especially in patients with leukemia. However, they have limited efficacy in solid
tumors. One barrier to success is the ability of ACT to penetrate the solid tumor microenvironment (TME),
where adoptive T cells often encounter resident suppressive immune cell lineages. The administration of
lymphodepleting conditioning in the form of chemotherapy, fludarabine/cyclophosphamide (FLU/CY) prior to
the infusion of T cells is a critical step to ensure T cell engraftment and persistence. The addition of total body
irradiation (TBI) to FLU/CY can further enhance lymphodepletion but comes at a cost of off-target toxicity.
Thus, the use of an agent that can more selectively lymphodeplete may improve the efficacy of ACT without
increased off-target toxicity. LLP2A is a peptidomimetic small molecule with a high affinity for very late antigen-
4 (VLA-4), expressed at high levels in lymphocytes and several cancers including melanoma and
neuroblastoma. Here, we propose to test VLA-4–targeted 67Cu-LLP2A radionuclide therapy (TRT) as a single
agent or in combination with dose-reduced (DR)-FLU/CY prior to ACT in two syngeneic solid tumor models
(pmel-1/hgp100 B16 melanoma and GD2 CAR/NXS-2 neuroblastoma model). We hypothesize that the
combination of 67Cu-LLP2A + DR-FLU/CY is a more effective lymphodepleting regimen than FLU/CY alone
(Hypothesis 1). We also hypothesize that 67Cu-LLP2A TRT can reduce tumor burden through direct radiation-
induced cell death and can facilitate T-cell mediated killing. We hypothesize that this new 67Cu-LLP2A
conditioning regimen will extend the survival of mice with VLA-4–expressing solid tumors treated with ACT
through greater penetration and activity of adoptive T cells within solid tumors (Hypothesis 2). To prove this, in
Aim 1, we will use state-of-the-art dosimetry and biodistribution studies to determine the dose where 67Cu-
LLP2A as a single agent or combined with DR-FLU/CY can achieve adequate lymphodepletion for ACT without
causing toxicity as well reduce tumor burden through direct cytotoxic effects. Then in Aim 2, we will examine
the ability of systemically administered 67Cu-LLP2A to enhance the efficacy of ACT in two syngeneic solid
tumor models. After completion of these aims, we will demonstrate that 67Cu-LLP2A TRT has the potential to
redefine current conditioning approaches for ACT and improve the outcomes of patients with solid tumors.
Terms: <21+ years old><A/J Mouse><Adoptive Cell Transfers><Adoptive Cellular Immunotherapy><Adoptive Immunotherapy><Adult><Adult Human><Affinity><Behavior Conditioning Therapy><Behavior Modification><Behavior Therapy><Behavior Treatment><Behavioral Conditioning Therapy><Behavioral Modification><Behavioral Therapy><Behavioral Treatment><Binding><Biodistribution><Body Tissues><CAR T cells><CAR modified T cells><CAR-T><CAR-Ts><CAT scan><CD49d-CD29><CITE sequencing><CITE-seq><CITEseq><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><CT X Ray><CT Xray><CT imaging><CT scan><CTX><CYCLO-cell><Cancers><Carloxan><Cas nuclease technology><Cell Body><Cell Death Induction><Cell Lineage><Cells><Cellular Indexing of Transcriptomes and Epitopes by Sequencing><Cellular immunotherapy><Childhood><Ciclofosfamida><Ciclofosfamide><Cicloxal><Clafen><Claphene><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Computed Tomography><Conditioning Therapy><Cycloblastin><Cycloblastine><Cyclophospham><Cyclophosphamide><Cyclophosphamidum><Cyclophosphan><Cyclophosphane><Cyclophosphanum><Cyclostin><Cyclostine><Cytophosphan><Cytophosphane><Cytoxan><Disease remission><Dose><Endoxan><Endoxana><Enduxan><Engraftment><Ensure><Failure><Fosfaseron><Future><Genoxal><Genuxal><Image><Immune><Immune mediated therapy><Immunes><Immunologically Directed Therapy><Immunotherapy><In Vitro><Infusion><Infusion procedures><Integrin Heterodimer alpha4beta1><Integrin alpha(4)beta(1)><Integrin alpha4beta1><Integrin α4β1><Label><Ledoxina><Lymphatic cell><Lymphocyte><Lymphocytic><Malignant Melanoma><Malignant Neoplasms><Malignant Tumor><Measures><Mediating><Melanoma><Mice><Mice Mammals><Mitoxan><Modeling><Molecular Interaction><Murine><Mus><Myelogenous><Myeloid><Neosar><Neural Crest Cell><Neuroblastoma><Organ><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Penetration><Phenotype><Procytox><Proliferating><Radiation><Radionuclide therapy><Refractory><Regimen><Remission><SPECT><SPECT imaging><Sendoxan><Single-Photon Emission-Computed Radionuclide Tomography><Site><Solid Neoplasm><Solid Tumor><Syklofosfamid><T cell based therapeutics><T cell based therapy><T cell directed therapies><T cell targeted therapeutics><T cell therapy><T cells for CAR><T-Cells><T-Lymphocyte><T-cell therapeutics><T-cell transfer therapy><Testing><Tissues><Tomodensitometry><Total Body Irradiation><Toxic effect><Toxicities><Translations><Tumor Burden><Tumor Cell><Tumor Load><VLA-4><Validation><Very Late Activation Antigen-4><Very Late Antigen-4><Whole-Body Irradiation><Whole-Body Radiation><X-Ray CAT Scan><X-Ray Computed Tomography><X-Ray Computerized Tomography><Xray CAT scan><Xray Computed Tomography><Xray computerized tomography><Zytoxan><adoptive T cell transfer><adoptive T-cell therapy><adoptive cell immunotherapy><adoptive cell therapy><adoptive cellular therapy><adulthood><behavior intervention><behavioral intervention><cancer microenvironment><catscan><cell killing><cell-based immunotherapy><cellular indexing of transcriptomes and epitopes by single cell sequencing><chemotherapy><chimeric antigen T cell receptor><chimeric antigen receptor><chimeric antigen receptor (CAR) T cells><chimeric antigen receptor T cells><chimeric antigen receptor fusion protein T-cells><chimeric antigen receptor modified T cells><computed axial tomography><computer tomography><computerized axial tomography><computerized tomography><conditioning><cost><cytotoxic><dosimetry><early clinical trial><early phase clinical trial><fludarabine><global gene expression><global transcription profile><imaging><immune cell therapy><immune clearance><immune elimination><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><improved><improved outcome><in vivo><infusions><leukemia><lymph cell><malignancy><neoplasm/cancer><neoplastic cell><non-contrast CT><noncontrast CT><noncontrast computed tomography><novel><patient oriented outcomes><pediatric><peptide mimetic><peptide mimic><peptidomimetics><pre-clinical><pre-clinical study><preclinical><preclinical study><preconditioning><radiation risk><risk mitigation><single photon emission computed tomography><small molecule><success><therapeutic T-cell platform><therapeutic radionuclide><thymus derived lymphocyte><transcriptome><translation><tumor><tumor microenvironment><validations>