LN-Cast, Lepton’s proprietary, miRNA-based technology platform (the “Castling Technology”), is a breakthrough technology for manipulation/engineering of miRNA expression by application of Gene Editing Technologies (GETs),in particular CRISPER-CAS9, to create ex vivo, products that modify gene expression for enhanced efficacy and longevity (reduced exhaustion) of cell-based therapies, such as Adoptive Cell Transfer – mediated therapies. The platform is protected by Lepton’s PCT patent application.
The method is in essence, counter-manipulating/ modifying the microRNAs (miRNAs)’ expression patterns imposed by the disease, by editing their genetic loci, ex vivo, in cells, such as T-cells, to improve their functionality. This is performed by simultaneously up-regulating a desired (“beneficial” or “good”) miRNA and shutting down/ down-regulating an undesired (“harmful” or “bad”) miRNA, in a single editing event. The miRNA pair is carefully selected such that the “harmful” member of the pair is transcriptionally induced in pathological state and orchestrates activation of gene network(s) that mediate(s) the unwanted phenotype(s); and the “beneficial” member is under expressed or unchanged in the pathology but, if upregulated ectopically, can activate gene network(s) that counteract(s) the unwanted pathological phenotype(s).
Initially the Castling Technology will be used to achieve better T-cell functionality in cancer treatment. The initial indications contemplated to be developed are blood cancers. Diffuse Large B-cell Lymphoma (DLBCL) is an example of such indication. Several LN-Cast permutations were identified and are examined.
The CAR T-cell therapy success rate is today about 30% to 40% for lasting remission[i]. Broad use of CAR T-cell therapies is limited by biological and logistical drawbacks, including potential for life-threatening toxicities, challenges related to manufacturing a patient-specific product, high costs and inadequate reimbursement, and incomplete or unstained disease response caused, among others, by the exhaustion of the immune cells.[ii].
With its carefully selected miRNA pairs, Lepton’s LN-Cast potentially could overcome the inadequacy of current CAR-T cell therapies for cancer, in particular exhaustion of CAR-T cells, via a single editing event, thus maintaining CAR –T cells persistence and ability to secret pro-inflammatory cytokines.
The simultaneous and reciprocal impact on genetic networks regulated by two different miRNAs is expected to have more significant therapeutic effect compared to single manipulations, improve safety and the cost effectiveness of the treatment.
Please link here for a brief overview of the technology. The Company has accomplished the in vitro POC of the novel technology.
[i] https://www.uchicagomedicine.org/forefront/cancer-articles/a-walking-miracle-car-t-cell-therapy
[ii] Rafiq, S., Hackett, C.S. & Brentjens, R.J. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat Rev Clin Oncol 17, 147–167 (2020). https://doi.org/10.1038/s41571-019-0297-y
[iii] Cancer Stat Facts: NHL — Diffuse Large B-Cell Lymphoma (DLBCL), National Cancer Institute https://seer.cancer.gov/statfacts/html/dlbcl.html
[iv] Al-Mansour, Mubarak et al. “Efficacy and safety of second-generation CAR T-cell therapy in diffuse large B-cell lymphoma: A meta-analysis.” Molecular and clinical oncology vol. 13,4 (2020): 33. doi:10.3892/mco.2020.2103
[v] Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA, Mackall CL. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124:188–195. doi: 10.1182/blood-2014-05-552729.
[vii] https://www.cancer.org/cancer/hodgkin-lymphoma/about/key-statistics.html
[viii] https://archive.cancerworld.net/e-grandround/immunotherapy-in-relapsed-refractory-hodgkin-lymphoma/#:~:text=The%20treatment%20of%20Hodgkin%20lymphoma,will%20eventually%20die%20of%20it.
[ix] https://seer.cancer.gov/statfacts/html/dlbcl.html