Cellular immunotherapy currently achieves significant efficacy in chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin’s lymphoma, and multiple myeloma. The first CAR-T treatment (KymriahTM) was approved by the FDA on August 31, 2017 for the treatment of two or more relapses under the age of 25 in patients with B-cell precursor acute lymphoblastic leukemia (B-ALL). The patient, and in May 2018, was approved a second indication for relapsed or refractory large B-cell lymphoma.
Kite’s Yescarta (KTE-C19) became the second FDA-approved CAR-T therapy on October 18, 2017 for the treatment of adult patients with certain types of large B-cell lymphoma (DLBCL). Both products have become important milestones in the history of cellular immunotherapy.
According to Novartis and Gilead’s first quarter earnings report for 2018, Kymriah and Yescarta achieved sales of $12 million and $40 million, respectively, and nearly 30 and 130 treatment cases were converted according to the price.
However, in the field of solid tumor treatment, the current CAR-T therapy is not satisfactory. Although the major institutions are striving to overcome difficulties, the efficacy has always been unsatisfactory. The main difficulties are:
1) It is still difficult to obtain solid tumor specificity. Most of the antigens that have been obtained are tumor-associated antigens (TAAs), so there is a risk of off-target effects (Off Target on Tumor);
2) another aspect of off-target effects is that resident memory T cells (Trm) accumulate in tumor tissues. More Tcm needs to be converted to Trm;
3) CAR-T cells require stronger cytokines and chemotactic factors that are more chemotactic.
At present, some institutions are exploring some solutions, including:
1) using Runx3 transcription factors, or modifying CAR (such as 7×19 CAR-T cells) to enhance the transcriptional expression of cytokines and chemokines, or recombining with IL7×CCL19. Modification to CAR-T significantly enhances the ability of CAR to recruit T cells, NK cells, DC cells, etc. to accumulate in tumor tissues;
2) Combine reversal of immunosuppressive molecules, such as the combination of PD-1 antibodies to enhance CAR-T, DC cells, etc. The anti-tumor effect, such as the PD-L1:CD28 chimeric receptor, converts the PD-L1 inhibitory receptor into a costimulatory receptor via the transmembrane and cytoplasmic protein domains of PD-L1 and CD28.
According to statistics, there are 11 cell immunotherapy products in the field of liver cancer, mostly in the early stage of clinical, and all are single indications for liver cancer. However, since a large number of cellular immunotherapy products are carried out by medical institutions themselves, it is difficult to make accurate statistics, so the number of researched varieties in this study will be less than the number of actual varieties under study.
Specifically, the liver cancer project of cell immunotherapy is mostly in clinical stage I-II, and the target is concentrated. The drug targeting glypican-3 target is the most, with 5, followed by CEA target and AFP target; the main mechanism of action is There are relatively few studies on CAR-T, TCR-T cell therapy and NK cell therapy.
The research and development institutions for cellular immunotherapy are divided. In the field of liver cancer, the development of cellular immunotherapy is based on start-up companies. Considering the R&D team of each enterprise and the technology, financial strength and the existing sales channels of the enterprise, the main problems faced by the start-up pharmaceutical enterprises are that the products are in the early stage, the risk of clinical development is large, the funds are limited, and there is no basis for sales channels. The market promotion ability is weak in the future. For medical institutions, the main problem is the lack of financial strength, and medical institutions have no drug promotion and sales channels. After a certain period of product research, it is very likely that the product rights will be sold to pharmaceutical companies.
At present, the Green Cross R&D team is strong in cell immunotherapy companies. The unnamed cell therapy and Adapt Sorrento Therapeutics are rich in financial support and can promote product development. In medical institutions, Roger Williams Medical Center has a strong R&D team and research capabilities, and is likely to be more marketable in the future. However, due to the lack of large-scale pharmaceutical companies involved in cellular immunotherapy for liver cancer, the current R&D institutions are lacking in sales capacity. It is expected that in the future, as the products mature and favorable clinical data are announced, large pharmaceutical companies will cooperate. Or participate in the form of investment, mergers and acquisitions, and promote the sales and promotion of cellular immunotherapy.