Since the approval of two CAR-T therapies in 2017, the enthusiasm for cell therapy has rapidly increased and the research and development pipeline has flourished across the globe. At present, in the field of tumor immunotherapy, the pipeline size of CAR-T cell therapy has been ranking first, even more than that of immunomodulatory drugs such as PD-1 monoclonal antibody.

Against such backdrop, Dr. Tang Yu from the Cancer Research Institute (CRI) conducted an in-depth analysis of its pipeline and analyzed the most interesting targets and treatment methods. Recently, this analysis report was published in the journal Nature Reviews Drug Discovery.

CAR-T therapy alone accounts for half of the total

After a statistical analysis, Dr. Tang’s team found that there are 1011 cell therapies that have been approved or are under development worldwide. Among them, CAR-T therapy exceeds 50% with the number of 568, which surpasses the sum of the other types of therapy (such as TCR-T cell therapy, tumor infiltration lymphocyte therapy, etc.). This, to some degree, also reflects the industry's enthusiasm for CAR-T therapy.

Most of the 568 CAR-T therapies are still in the early stages of development. As noted by the researchers, there were 264 CAR-T therapies in the preclinical phase and 150 in the phase 1 clinical phase. Adding the two together, they accounts for more than 70% of the current CAR-T therapy pipeline.

It is worth mentioning that the CAR-T therapy pipeline is still growing rapidly. In an analysis last year, the researchers found there were 404 CAR-T therapies, a figure that grew by 164 this year, an increase of nearly 40%. Judging from the research and development stage, the proportion of early clinical treatments last year was also about 70%, indicating that there is a constant advancement in CAR-T therapy. In fact, the number of CAR-T therapies in Phase 2 clinical and subsequent stages has indeed increased from 110 to 154.

The hottest target: CD19 tops the list

In an analysis last year, CD19 was the hottest target in the cell therapy line. This year, it topped the list and once again became the most popular target. According to statistics, there are currently 142 treatments targeting CD19, including 130 CAR-T therapies.

In terms of number, tumor-associated antigen (TAA) is the second largest type. For this type of target, the researchers' R&D direction is mainly focused on tumor infiltrating lymphocytes, T cells targeting TAA/TSA (tumor specific antigen), or natural killer cells, instead of CAR-T therapy. Tumor-associated antigens represent a range of targets. If we have to rank them, BCMA takes the second place just after CD19, and there are 36 in-situ treatments, an increase of 11 compared with last year. It should be pointed out that BCMA is attracting more and more attention, given recent positive clinical results.

China and the United States together have 70% of the pipeline

In the study, the most popular research areas of cell therapy are also investigated. They pointed out that the United States and China are currently the most active countries in developing cell therapy, and the number of approved and researched products exceeds 400 and 300 respectively. The sum of the two accounts for about three-quarters of all cell therapies worldwide.

Interestingly, the cell therapy pipelines in both countries have shown a different trend in the R&D phase. In the United States, most cell therapies are preclinical, while in China, most cell therapies have entered the clinical stage. The authors also pointed out in the review that 47% of China's current cell therapy is developed by biotechnology companies, a significant increase from 38% last year, reflecting the rapid development of China's cell therapy industry.

Challenges in the future

In the closing section of this review, the authors discuss the prospects of cell therapy for solid tumors. Currently, approximately 90% of cancer cases worldwide are solid tumors. However, since 1993, only about half of the cell therapy clinical trials have been conducted on solid tumors, and many clinical trials have focused on melanoma, central nervous system tumors, and liver cancer. In other words, the biggest challenge facing all of us is that current cell therapies do not work well for many solid tumor types.

There are many reasons behind this, including the heterogeneity of antigens, the immunosuppressive microenvironment of solid tumors, and the thick extracellular matrix, all of which make cell therapy difficult to effect. Therefore, the combination of other tumor immunotherapy (such as checkpoint inhibitors) may bring new breakthroughs. In addition, cell therapy beyond CAR-T therapy may also be able to create new treatment modalities.

Summary

Although the vigorous development of cell therapy is expected to bring more innovative therapies for treating patients, there is no denying that there are many “repetitive tasks” in the current pipeline. It is very likely that CAR-T therapy targeting CD19 may lead to redundancy.

Therefore, measures like finding a target other than CD19, or developing a model other than CAR-T therapy, or using the CRISPR gene editing system, or using induced pluripotent stem cell technology, are expected to bring cell therapy into a new era.

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