Two recently published studies provide preclinical insights into ‘training’ CAR T cells that may potentially lead to more effective and less toxic immunotherapy approaches
Over the last decade, immune-based strategies that harness, fortify, and boost a patient’s immune system to target, attack and destroy cancer cells, are increasingly stepping up as the fifth pillar of cancer therapy alongside the three mainstays of treatment: surgery, chemotherapy, and radiation therapy, and more recently, the expanding suite of targeted therapies.
Immune checkpoint inhibitors (ICIs), particularly in combination, are already used to treat several types of cancer and are expected to benefit an increasing number of patients as we collectively advance insights into tumour heterogeneity, overcome the immune suppressive effects of the tumour micromilieu, deepen our understanding of the extracellular matrix on patient response to therapy, seek out robust predictive biomarkers, as well as identify new proteins specific to different cancers and design drugs to target them.
Chimeric antigen receptor (CAR) T cell therapy is another rapidly evolving form of immunotherapy. While still in its infancy and not as widely used as ICIs, this novel contender is also making headlines in both lay and specialized media. The first CAR T cell therapy was approved by the U.S. Food and Drug Administration in 2017 for the treatment of acute lymphoblastic leukemia, with EMA approval one year later. A total of six CAR T cell therapies are now approved for the treatment of lymphomas, some other forms of leukaemia, and, most recently, multiple myeloma.
While continued investigations are naturally warranted to improve long-term survival in an increasing number of patients, these agents are nonetheless transforming the treatment of blood cancers. The same cannot be said however in unleashing the potential of cellular immunotherapy in solid tumours. Well, not yet.
The preclinical promise of CAR T cell therapy in solid tumours
Research on CAR T cell therapy is moving at a rapid pace to expand its application and use to more cancers by tackling several obstacles in this field. Current challenges include counteracting components of the hostile tumour microenvironment, the engineering of these cancer-killing T cells to better target specific proteins and traffic to and infiltrate tumours, as well as reduce associated and potentially life-threatening toxicities such as cytokine storm.
Investigators across the globe are leading efforts to identify new avenues and potential solutions that may help to ultimately position this immunotherapy as a powerful armoury in more effectively treating appropriately selected patient with advanced solid tumours.
Illustrative of these preclinical efforts are two recently published papers.
Spearheaded by Carl H. June, one of the pioneers in the development of CAR T cell therapy that led to the FDA approval of the first CAR T therapy, results of a study published in Science Advances (Sci Adv. 2023 Jan 13;9(2):eade2526) show that CAR T cells can be safely and effectively used to clear residual cancer cells after surgery and may thus enhance the effectiveness of surgery for solid tumours.
Published in Science, results of preclinical research carried out by Greg M. Allen and investigators at the University of California San Francisco, show how synthetic biology can be used to design CAR T cells that attack solid tumours and thus overcome the challenge of their immunosuppressive microenvironment that inhibits T cell infiltration, activation, and proliferation (Science. 2022 Dec 16;378(6625):eaba1624).
CAR T as a potential eliminator of residual cancer cells post-surgery
Due to factors including tumour bulk, tumour anti-immune defenses, and on-target off-tumour toxicity, solid tumours represent a challenge for CAR T therapies. Spurred by a previous study by other researchers that explored the use of CAR T cells in removing residual cancer cells after surgery in a mouse model of brain cancer (Sci Adv. 2021 Oct 8;7(41):eabg5841), Carl H. June and colleagues at the University of Pennsylvania Perelman School of Medicine, Philadelphia, put this approach to the test in two partial resection xenograft models of triple-negative breast cancer and pancreatic ductal carcinoma, using mesothelin-specific CARTs.
Pointing to a potential new application of CAR T cell therapy in solid tumours, preclinical data from this study suggest that the local delivery of CAR T cells in a fibrin glue-based carrier could be used as adjuvant therapy after surgery.
Specifically, by applying this special gel to surgical wounds in mice following partial tumour resection, these CARTs were effective in clearing residual cancer cells in almost all cases, resulting in significantly improved survival when compared to mice treated with surgery and CARTs without fibrin glue. They also reported less on-target off tumour toxicity, with no wound healing complications observed in mice.
These encouraging results have paved the way for a clinical trial in patients with locally advanced breast cancer. The authors conclude that this novel approach could be broadened to deliver other cellular therapies in addition to CAR T cells that might further boost the overall antitumor response.
Enhancing CAR T cells to attack solid tumours
Aimed at overcoming the challenge of immunosuppressive microenvironments in solid tumours, Greg M. Allen and colleagues, recently developed enhanced CAR T cells that can recognise a tumour antigen and also have a second receptor (synthetic Notch receptor) that can cause the T cell to release cytokine interleukin-2 (IL-2), promoting local proliferation of T cells despite the tumour’s immunosuppressive effects, but only when they are in direct contact with tumour cells.
In mouse models this strategy facilitated infiltration of these reconfigured cells into solid pancreatic and melanoma tumours, resulting in a robust antitumor response and improved survival in these challenging immune-competent tumour models. In this study, the authors also report that unlike systemically delivered IL-2 treatment, these local cell-based IL-2 circuits do not show toxicity. They conclude that these types of engineered cytokine delivery circuits may provide a general strategy for driving effective CAR T therapies against immune-suppressed solid cancers.
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Just how these preclinical insights may ultimately translate in improving outcomes for patients with advanced solid tumours remains to be seen. While much work still needs to be done in ‘training’ CAR T cells to traffic to, more effectively infiltrate, and successfully combat solid cancers, we have every reason to be optimistic that such research will ultimately lead to the development of more effective, precise and less toxic cellular immunotherapies.
