LN-Cast, Lepton’s Proprietary Castling Platform Technology
Lepton’s miRNA-based proprietary general technology platform. LN-Cast serves to manipulate/engineer miRNA expression for enhanced efficacy and longevity of cell-based therapies (US patent application filed).
Initially it will be used to achieve better T-cell functionality in cancer treatment. For such purpose, miRNA pairs were selected such that one is a “harmful” miRNA (that is highly expressed when triggered by cancer cells presence and thereby promotes the expression of the immune exhaustion phenotype) and the other is a “beneficial” miRNA (the expression of which is reduced by the close proximity of the cancer cells). The “harmful” miRNA is replaced by the “beneficial” miRNA by a single gene-editing event thereby gaining a double effect on T-cell functionality.
Several LN-Cast permutations were identified and are examined, and we expect to achieve proof of function in vivo within about 8 – 10 months.
The CAR T-cell therapy success rate is today about 30% to 40% for lasting remission[i]. Challenges including significant toxicity and insufficient efficacy and applicability of CAR T cell therapy are related mainly to the current engineering strategies and CAR-T designs used[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.
Products based on LN-Cast
LN- Cast- 01 for Diffuse Large B-cell lymphoma (DLBCL)
DLBCL is a fast-growing, aggressive form of Non-Hodgkin Lymphoma (NHL). DLBCL is fatal within months if left untreated. It is the most common type of NHL diagnosed in the Western hemisphere, representing 30-40% of all NHL cases diagnosed every year in the United States. The incidence and rate of deaths per 100,000 of DLBCL is 5.6 respectively 1.8 per per year[iii]. With treatment the mean overall survival at 5 years is currently 63.8% in the USA. About 1/3 of treated patients’ relapse. Some 10% have refractory disease. High-dose immunotherapy followed by autologous stem cell transplantation is the standard care for relapsed/refractory (RR) patients with DLBCL. However, >60% of patients are ineligible for a transplant, presenting a therapeutic challenge.[iv] CAR T therapies have been approved for patients with DLBCL, however, this therapy is also associated with unexpected toxicities that can be life-threatening, including cytokine release syndrome (CRS) and neurotoxicity[v] CD19 CAR T related toxicities include hematological, metabolic, infectious, and neurological complications[vi].
Other Remarkable Products Based on LN-Cast
- Additional LN-Cast permutations of miRNA pairs (stable allogenic CAR T cells or off the shelf)
- Solid tumors
- Potentially additional blood cancers, such as refractory Hodgkin’s lymphoma, acute myeloid leukemia, multiple myeloma
- miRNA castling in T-regulatory (Treg) or CAR-Treg cells for the treatment of systemic lupus erythematosus (SLE) and/or allergic asthma
- Gene/miRNA castling – replacement of a “harmful” gene (e.g. PD1 and/or CTLA-4) by a “beneficial” miRNA in CAR-T / CAR-NK cells
- miRNAs castling in hepatocytes for the treatment of hypercholesterolemia and CVD
For the first follow on indication, LN-Cast 02, we have selected refractory Hodgkin’s lymphoma, a cancer of the lymphatic system as the first follow on disease for development of LN-Cast based therapy[vii]. Close to 9000 new cases and almost 1000 deaths are registered yearly in the USA. Up to 35% of patients have primary refractory or relapsed Hodgkin lymphoma, and a proportion will eventually die of it[viii].
[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.