Chapter 91
Cancer — 18
There are currently more than five hundred clinical trials of CAR-T therapy to approach solid cancer, trying to override the challenges of getting the engineered T cells into the tumor, much more diversity of mutations, and overcoming the local suppression of the immune response. But scientists are pursuing many ways to override these challenges, including CRISPR genome editing to activate thousands of genes in the T cells or express proteins with enhanced cell penetration. They are also aiming to rejuvenate T cells that are considered exhausted or dysfunctional because they’ve lost their ability to fight cancer cells. These are new strategies to enhance their fitness or ensure they are better protected (cutely called “armored” CAR-T cells). Researchers are exploring the use of naturally occurring mutations, not present in an individual’s cancer, to add to T cells as a means of revving up the immune response. And we’re learning about injecting a virus that specifically infects T cells to insert the genes needed to achieve T cell engineering within the body. On and off “suicide” switches can be programmed into the cells to limit cytokine release, a prime toxicity generator.
In addition to T cells, scientists are engineering other immune cells, such as CAR-macrophages and CAR-NK (natural killer cells). Current engineering of cells is laborious and expensive (estimated cost now at $500,000) since it involves removing cells from the person’s body, modulating them, and returning them. There is now considerable effort to move to off-the-shelf cell availability, by manufacturing cells that have powerful immune defense properties but are not derived from or specific to a patient. Such a strategy could markedly cut costs and time to treatment. In India, they are being provided at about one-tenth the cost. In Australia, Interius Biotherapeutics has initiated the first clinical trial of in vivo CAR-T, with an intravenous infusion of an inactivated lentovirus to insert antigens onto T cells and transform a person’s own immune cells to fight cancer. With the intensity of efforts and multiplicity of strategies, it is likely that we’ll see engineered cells become a mainstay of treatment for solid cancers in the years ahead.
There are a small number of T cell cancers that have cropped up after CAR-T therapy, about one per one thousand people treated, and via molecular markers, most appear to have been induced by the T cells, because the chimeric antigen receptor gene can be detected. Besides engineering T cells derived from a patient’s blood, there are also tumor-infiltrating lymphocytes, isolated and grown from a patient’s cancer tissue, the first of which was FDA approved in 2024 for advanced melanoma. Potential treatments for many other types of solid cancer are being pursued in clinical trials.
Which patients might benefit from which therapy, or what is emerging as multitudes of combinations of therapies, is being pursued with AI by integrating all of a patient’s data, to improve clinical trials testing the interventions, with multiple start-up companies that have cropped up for guiding clinicians on patient selection. Knowledge of how influential the gut microbiome is in cancer, and how that can be modulated, is laying the foundation for an improved, individualized approach. Use of a patient’s cancer cells in culture to form organoids can help predict response to therapy. Radiation therapy for cancer is one field that has been undergoing AI transformation, specifically decisions on treatment, planning, and delivery of radiotherapy.