Life Sciences & Biotechnology
Title : | Neoantigen specific T cell engineering for Cancer Immunotherapy using Nanotechnology |
Area of research : | Life Sciences & Biotechnology |
Principal Investigator : | Dr. Anuradha Gupta, Indian Institute Of Technology (IITBHU), Uttar Pradesh |
Timeline Start Year : | 2023 |
Timeline End Year : | 2025 |
Contact info : | anuradhagupta01@gmail.com |
Details
Executive Summary : | Neoantigen based cancer vaccines have emerged as therapeutic strategy to generate cancer-specific immune response by circumventing immune tolerance [Bear AS. Nat Commun 2021]. However, continuous availability of tumor-associated antigen at higher doses in lymph node residing antigen presenting cells (APCs) is the biggest challenge due to high proteolytic degradation and rapid clearance from the body; short half -life for neoantigen based cancer vaccine design. At times, weak immunogenicity of point mutation peptides is another concern. So, appropriate selection of tumor-specific antigen and its targeted delivery is the current demand. Almost 20% of human malignancies harbors the GTPases missense mutations in the RAS family particularly KRAS, NRAS and HRAS [Simanshu DK; Cell 2017]. Hence, KRAS G12 may be an ideal candidate due to high prevalence and conserved mutation, providing a unique opportunity for personalized vaccine design. Combining neoantigen vaccine with other check-point inhibitor therapies i.e. siRNA mediated down regulation of Cytotoxic T lymphocyte-antigen 4 (CTLA-4), a negative immune regulatory factor will increase the therapeutic efficacy of the cancer vaccine [Parry RV. Mol Cell Biol 2005]. Antigenic peptide delivery along with si-CTLA-4 via nanoparticulate approaches [Hou F. Nanomed: Nanotechnol Biol Med 2022] will lead to efficient antigen presentation and cross-priming of T cells as compared to soluble antigen administration. Among nanoparticles, mesoporous silica nanoparticles (MSN) coated with polymer poly lactic-co-glycolic acid (PLGA) will deliver the advantages of high antigen-payload, controlled release, biocompatible and biodegradable nature. Thus the cancer nanovaccine comprising of PLGA-MSNs could deliver the neoantigen and CTLA-4 siRNA efficiently to the APCs, educate the T cells against KRAS G12 neoantigen. Furthermore, downregulation of CTLA-4 will revert the tolerogenic T cells in to KRAS neoantigen-specific functional T cells, leading to robust cancer cell killing. Experimental methods will include the synthesis of MSNs and PLGA coating. Antigen and si-CTLA-4 will be loaded into porous nanoparticles. PLGA coating will prevent antigen and siRNA degradation, and provide controlled release. Cell line studies will include the neoantigen (KRAS G12) presentation by APCs, CTLA-4 downregulation and cytokine release. Further, animal immunization, and tumor progression studies will be performed to check the therapeutic efficacy of cancer nanovaccine.
Thus, the proposed work will lead to targeted delivery of KRAS G12 neoantigen with CTLA-4 siRNA and generation of potent neoantigen specific-cytotoxic (CD8+) T cell response. Inhibition of CTLA-4 during early T cell priming will favor the copious antigen- specific CD8+ T cell generation. Dual delivery of CTLA-4 siRNA in combination to KRAS G12 via PLGA-MSNs will prevent the immune escape mechanism of cancer cells and led to increased T cell mediated cancer cell killing. |
Organizations involved