Novel Molecular Targeted Radionuclide Therapies for Dosimetry-Guided Immunomodulation

用于剂量测定引导免疫调节的新型分子靶向放射性核素疗法

• 批准号: 10263245
• 负责人: JAMEY P WEICHERT
• 金额: $ 35.81万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10263245
• 关键词: 90Y; Affect; Anatomy; Antitumor Response; Binding; Biodistribution; Biological; Blood; Bone Marrow; Cancer Patient; Canis familiaris; Cell Count; Cellularity; Chelating Agents; Clinical; Companions; DNA Vaccines; Detection; Diagnostic Imaging; Disease; Dose; Dose-Rate; Exhibits; External Beam Radiation Therapy; FDA approved; FOLH1 gene; Goals; Image; Immune; Immune system; Immunologic Memory; Immunosuppression; Immunotherapy; In complete remission; Interferon Type I; Isotopes; Knowledge; Linear Energy Transfer; Location; Low Dose Radiation; Lymphopenia; Malignant Neoplasms; Measurement; Microscopic; Modality; Modeling; Molecular Target; Monoclonal Antibodies; Mus; Neoplasm Circulating Cells; Neoplasm Metastasis; Normal tissue morphology; Organ; Patients; Play; Predisposition; Property; Radiation therapy; Radioactive; Radioisotopes; Radiolabeled; Radionuclide therapy; Regulatory T-Lymphocyte; Risk; Role; Scanning; Site; Spleen; Stimulator of Interferon Genes; Testing; Therapeutic; Time; Toxic effect; Translating; Tumor Tissue; Tumor-infiltrating immune cells; Vision; analog; cancer cell; checkpoint inhibition; dosimetry; draining lymph node; immunoregulation; in situ vaccination; in vivo; metaiodobenzylguanidine; mouse model; neoplastic cell; novel; peripheral blood; pre-clinical; response; side effect; synergism; theranostics; treatment optimization; tumor; tumor immunology; tumor microenvironment; uptake; vector

PROJECT SUMMARY – PROJECT 1: Mounting preclinical and clinical evidence demonstrates that external beam radiation therapy (EBRT) can enhance the systemic anti-tumor response to immunotherapies (ImmRx) by modifying the tumor microenvironment (TME) in ways that enhance tumor immune susceptibility. Others and we have observed that in the setting of multifocal or metastatic disease this capacity of focal EBRT to elicit in situ vaccination (optimal at doses of 8-12 Gy) may be further enhanced by delivering low dose radiation (RT; 2-4 Gy) to all tumor sites. In this capacity, low dose RT may play a critical role in overcoming tumor-specific immune suppression from RT-sensitive immune lineages [e.g. regulatory T cells (Tregs)] and may also enhance the immune susceptibility of tumor cells at these disseminated sites by cGAS/STING activation of a type I interferon (IFN) response. The limited ability of EBRT to target all tumor sites without considerable risk of toxicity is a major hurdle that limits the capacity of EBRT to modulate the collective TME in this manner. In the setting of microscopic or metastatic disease, it is not possible to treat all TMEs with EBRT at the doses required for immunomodulation without also incurring lymphopenia. Consequently, a radiotherapy modality is needed that can deliver immunomodulatory RT doses to all tumor sites without triggering systemic immunosuppression. To meet this need, we hypothesize that molecularly targeted radionuclide therapy (TRT), a systemic form of radiotherapy combining a tumor-selective vector with a therapeutic radioisotope, will deliver immunomodulatory RT to all metastatic tumor sites resulting in significant tumor responses without systemic immune suppression. To effectively study these broad mechanisms requires a TRT agent with 1) selective uptake across a breadth of malignancy, 2) a theranostic capacity for delivery of paired isotopes that can be used for therapy and diagnostic imaging (e.g. 90Y and 86Y, respectively) to facilitate personalized dosimetry, and 3) the ability to bind and deliver diverse radionuclides to study the differential capacity of these to immunomodulate the TME of micro- and macro-metastases. Current FDA-approved TRTs are limited in their capacity to achieve this vision. We have developed a novel TRT vector, NM600, which is optimally suited for this broad application in dose-dependent immunomodulation and which has produced many complete responses including tumor specific immune memory induction in syngeneic murine tumor models when used in combination with checkpoint inhibition (Project 2), immunocytokine (Project 3), and DNA vaccine (Project 4) immunotherapies. Project 1 will investigate how the properties of different TRT vectors and radionuclides (e.g. linear energy transfer (LET), dose rate, and dose distribution) influence the TME and the host immune system in syngeneic mouse models relevant to each Project and also in companion canine cancer patients to assess whether parallel effects can be translated to a larger species. In Projects 2-4, this knowledge will be utilized to optimize the combination of TRT with each type of ImmRx and to elucidate biological mechanisms of observed synergies.

项目摘要-项目1：大量临床前和临床证据表明外部