Chimeric antigen receptor T-cell (CAR-T) therapies have demonstrated significant efficacy against certain blood cancers such as acute lymphocytic leukemia (ALL) and large B-cell lymphoma. Novartis, Gilead, and Bristol Myers Squibb are among the pharmaceutical companies which currently offer CAR-T therapies as a treatment for certain blood cancers. These commercial CAR-T therapies have gained regulatory approval in Canada and the United States, among other countries over the recent years.
One of the limitations of CAR-T treatments and existing research is the lack of efficacy observed against solid tumors. To date, there are no commercial CAR-T therapies approved for use to treat solid tumors in Canada. A number of challenges are present with targeting solid tumours. One notable challenge is known as tumour antigen heterogeneity. CAR-T treatments operate by targeting specific antigens, however for solid tumours not all tumour cells will express the antigen that is being targeted [1].
Moreover, the level of expression of the antigen can vary significantly between tumour cells [2]. This variability and lack of uniform expression of the targeted antigen reduces the impact of the CAR-T therapy. In addition, another difficulty in treating solid tumours is infiltration. CAR-T cells return into the blood stream, thereby contacting blood tumour cells more frequently [2]. However, with solid tumours the CAR-T cells may not be able to penetrate the tumour tissues [2, 3].
New research from Grosskopf, Labanieh [3] shows promising results through a new delivery mechanism for CAR-T cells intended to treat solid tumours. The researchers have created an injectable hydrogel to deliver both CAR-T cells and stimulatory cytokines [3]. For effective CAR-T therapy, the cells must be highly activated. The high cytokine concentrations can lead to severe toxicities if delivered directly into the blood stream. The hydrogel environment developed by Grosskopf, Labanieh [3] houses the CAR-T cells and cytokines at a location injected near the solid tumour. The activated CAR-T cells are able to pass through the hydrogels while the passive diffusion of the cytokines is inhibited [3]. This mechanism allows for the continual and more gradual release of CAR-T cells to target the tumour cells.
Furthermore, Grosskopf, Labanieh [3] also found that the hydrogel mixture did not need to be injected close to the tumour. In mice, the tumours took about twice as long to disappear when compared to administering the treatment near the tumour site [4]. Grosskopf, Labanieh [3] also note that the hydrogel is simple to create. The gel contains water and a polymer made of cellulose [4]. The simplicity of creating the hydrogel provides for the possibility of delivering such treatment within a hospital environment, similar to the point of care model used to deliver CAR-T treatment to patients within the CLIC-1901 trial in Canada.
This advancement in CAR-T research demonstrates new promise for the use of CAR-T cells to treat solid tumours. Thus far, CAR-T treatments for cancer treatments have been limited to hematologic malignancies. While further research is certainly needed to determine the potential tumour types that can be treated with this mechanism, these findings are important in advancing CAR-T treatments for solid tumours.
CAR-T research is innovative, and in Canada is supported by public funds. Through this innovative development, Canadians with rare cancers are finally been given hope for treatments for their unmet medical needs.
References
1. Albelda, S.M., Tumor Antigen Heterogeneity: The “Elephant in the Room” of Adoptive T-cell Therapy for Solid Tumors. Cancer Immunology Research, 2020. 8(1): p. 2-2.
2. Marofi, F., et al., CAR T cells in solid tumors: challenges and opportunities. Stem Cell Research & Therapy, 2021. 12(1): p. 81.
3. Grosskopf, A.K., et al., Delivery of CAR-T cells in a transient injectable stimulatory hydrogel niche improves treatment of solid tumors. Science Advances, 2022. 8(14): p. eabn8264.
4. Prillaman, M. Stanford engineers develop a simple delivery method that enhances a promising cancer treatment. 2022; Available from: https://news.stanford.edu/2022/04/08/gel-delivery-enhances-cancer-treatment/.
Photo credit: Drew Hayes (2017). Person Holding White Clear Container [Image]. https://unsplash.com/photos/tGYrlchfObE?utm_source=unsplash&utm_medium=referral&utm_content=creditShareLink
Written by: Faisal Ali Mohamed (PhD Student)