Immune checkpoint inhibitors (ICIs) vastly improved the outcome of various advanced cancers; however, many are less likely to respond to single-agent ICI. Tumors with low T-cell infiltration are "immunologically cold" and less likely to respond to single-agent ICI therapy. This diminished response is presumably due to the lack of neoantigens necessary to activate an adaptive immune response. On the other hand, an "immunologically hot" tumor with high T-cell infiltration has an active anti-tumor immune response following ICI treatment. Therefore, converting immunologically “cold: tumors to "hot" is an essential step in immunotherapy. There is a critical need for novel treatments and immunotherapeutic agents with this capability.
This invention is a novel strategy to induce immunologically "cold" tumors to become more readily targeted by a healthy immune system. A promising immunotherapeutic approach was developed called MBTA (Mannan - BAM, TLR agonists, Anti-CD40 antibodies). The MBTA strategy involves pulsing tumor cells with a combination of mannan-BAM (a polysaccharide derivative of mannan), TLR (Toll-like receptor) ligands, and agonistic anti-CD40-monoclonal antibody. This approach stimulates acute inflammatory responses in the tumor microenvironment, enhances tumor cell phagocytosis, and induces tumor-specific, adaptive immune responses. The tumor therapeutic efficacy of MBTA achieves increased survival rates by improving tumor regression, enhancing tumor-specific infiltrating lymphocytes, and developing immunological memory in colon cancer mice models. Treatment with mouse colon cancer-MBTA vaccines successfully generates potent and systemic tumor-specific immune response when administered subcutaneously. In addition, subcutaneous delivery generates striking efficacy against distal, untreated tumors.
This novel immunotherapeutic approach has tremendous potential to brings solutions to the following critical problems in cancer immunotherapy:
1. Converts immunologically cold to hot tumors.
2. Supports the development of tumor-specific adoptive immunotherapies.
3. Makes it possible to generate tumor-specific lymphocytes and identify tumor-specific epitopes for adoptive immunotherapies.
- Stimulation of the innate and adaptive immune systems to elicit rejection of primary and distant tumors
- Creating a potent antitumor immune response resulting in improved tumor growth control and survival
- Personalized tumor vaccine
- Immunological memory against tumor
There are no technologies, products or processes currently on the market that accomplish the purposes of this invention.
Zhengping Zhuang MD PhD (NCI), Karel Pacak MD, PHD, D. Sc. (NICHD), Rogelio Medina (NCI), Herui Wang Ph.D (NCI), Jan Zenka PH.D (University of South Bohemia), Winson Ho M.D. (Little Bridge Therapeutics)
- Medina R, et al. Induction of Immune Response Against Metastatic Tumors via Vaccination of Mannan-BAM, TLR Ligands and Anti-CD40 Antibody (MBTA). (PMID: 33709018) corresponding to NIH Ref. E-003-2020.
- Lookian PP, et al. Mannan-BAM, TLR Ligands, Anti-CD40 Antibody (MBTA) Vaccine Immunotherapy: A Review of Current Evidence and Applications in Glioblastoma. (PMID: 33810617) corresponding to NIH Ref. E-003-2020.
- Uher O, et al. Mannan-BAM, TLR ligands, and anti-CD40 immunotherapy in established murine pancreatic adenocarcinoma: understanding therapeutic potentials and limitations. (PMID: 33855601) corresponding to NIH Ref. E-003-2020.
- U.S. Provisional: U.S. Provisional Patent Application Number 62/946,934 , Filed 11 Dec 2019