Around 500 million years ago, life on Earth underwent a phase of rapid diversification that led to the formation of complex biological structures and the appearance of new groups of organisms. This crucial event for evolution captured the imagination so strongly that it became a metaphor. ‘CARs in 2025: the Cambrian explosion continues’, in fact, is the title chosen by Michel Sadelain for the lecture hosted by GEN (Genetic Engineering & Biotechnology News) on 29 January. The most exciting branch of immunotherapy, using engineered T lymphocytes to efficiently and selectively attack cancer cells, is experiencing a boom in new approaches and applications.

The French-born scientist helped lay the foundations of the field, his group was the first to report findings of dramatic remissions in patients with acute lymphoblastic leukemia following treatment with CD19-targeted T cell, and has continued to work on optimizing these technologies and bringing them to the bedside.

Today there are half a dozen CAR-T therapies approved in Europe: Abecma, Breyanzi, Carvykti, Kymriah, Tecartus, and Yescarta (plus Aucatzyl in the US). They fight blood cancers and are intended for patients whose disease has returned or has stopped responding to previous treatment. Here is the list of indications with complete remission rates, as presented by Sadelain, who recently left Memorial Sloan Kettering Cancer Center in New York for Columbia University: large B cell lymphoma (38-63%), acute lymphoblastic leukemia (82-85%), multiple myeloma (23-90%), mantle cell lymphoma (78%), follicular lymphoma (80%).

The number of applications is set to increase thanks to next-generation CAR-Ts. The beauty of CAR receptors is that they are modular, so by changing domains, different ‘living drugs’ can be produced. T-cells were originally engineered with retroviral vectors, then lentiviral vectors, and the toolbox now includes transposons and, above all, CRISPR.

“There is still much research needed to better understand what is optimal in one disease setting or another. Much of the excitement around this technology is precisely that it can be declined in so many ways and adapted to very specific needs”, explains Sadelain.

One ingredient added to the classic recipe, for example, is the 1XX module, which seems to guarantee potency and persistence even at low doses, thus minimizing toxicity. “We used this new CAR in 28 patients, achieving complete remission in three-quarters of them. This innovation is part of the Cambrian explosion and one we intend to further develop. In mouse models of ovarian and breast cancer, this CAR outperformed the classic types”.

Then there is the issue of sensitivity, meaning the number of target molecules that need to be at the surface of the cell for that cell to be efficiently targeted and ultimately destroyed by the CAR-T. “We report that 1XX is far more sensitive than conventional receptors”.

In nature, T cells are limited to having only one receptor (single targeting), but in the laboratory, this constraint doesn’t exist. The logic gating approach includes a range of possibilities: OR-gate, AND-gate, NOT-gate, IF-THEN-gate, and IF-BETTER-gate. The last one is beginning to be tested in acute myeloid leukemia: “We initiated a clinical trial at different doses, I can only say please stay tuned”, says Sadelain.

Another goal on the horizon is to develop CAR approaches that not only eliminate cancer cells but also perform other functions, such as modulating the microenvironment or recruiting other immune effectors.

Today’s therapies are autologous, i.e. they are based on the use of cells taken from the patient himself, and their modification carried out outside the body (ex vivo). The trend is to speed up the process: “We are going from 7 to 3 days and maybe we can go even lower”.

Furthermore, the possibility of using allogeneic cells harvested from compatible healthy donors or derived from pluripotent stem cells grown in a bioreactor is also emerging. Another challenge is ‘in vivo’ production, directly inside the patient’s body, using lipid particles or viral vectors.

Besides tumors, CAR-T applications can play a role in autoimmunity, possibly in some severe infections, to resolve challenges in transplantation and ultimately facilitate a number of regenerative medicine strategies.

We have seen the wonderful work reported by Georg Schett in Germany for refractory systemic lupus erythematosus. Another strategy also deserves special mention, Scott Low and Corina Amor targeting senescent cells which, if not cleared, can promote diseases such as liver fibrosis.

Research is advancing and exploring different directions: “Acute myeloid leukemia and solid tumors are still challenges that remain to be tackled, but there are good reasons to be optimistic”, argues Sadelain.

And while the high price for today’s CAR-T therapies is at the risk of hindering the development of the field, there are many shots on go to develop new transformative manufacturing processes which Sadelain hopes will make these therapies more available for a number of pathologies. “There is much much more to do in the field of CAR T cells”. The best, hopefully, is yet to come.

[This text was published in Italian on the website of Osservatorio Terapie Avanzate]