Advancing Cell Therapy Success in Solid Tumors
CAR-T cell therapy has proven highly successful in treating hematological cancers and the race is on to extend cellular therapies to a wider range of cancers.
August 10, 2022
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Since the approval of Kymriah in 2017, cellular therapies have transformed treatment for some cancer indications. These initial successes have inspired a wave of research, with a host of new therapeutics in development and clinical trials. To date, five CAR-T therapies have been approved by the FDA for six indications, all for the treatment of liquid tumors or blood cancers including forms of lymphoma, leukemia, and multiple myeloma. Of these therapies, four target CD19, a receptor expressed on the surface of the cancer cell, and one, Abecma for the treatment of multiple myeloma, targets the B-cell maturation antigen (BCMA), which is also present on the cell surface.  It is the very accessibility of these types of cancer cells (circulating in the blood) coupled with the availability of the target antigen (located on the cell surface) that renders these particular cancers so amenable to treatment with CAR-T cell therapy.
Despite the early success of CAR-T in the treatment of blood cancers, there has been little success in translating this technology to the treatment of solid tumors, an area that represents a far larger opportunity with many more cancer indications that would benefit from effective cellular therapies.
While data is limited, there has been success utilizing CAR-T for the treatment of solid tumors. As early as 2016, Brown et al  reported the treatment of brain tumors with CAR-T cell therapy in a patient with highly aggressive recurrent glioblastoma, observing a dramatic reduction in the size of intracranial and spinal tumors until the tumors were no longer measurable via MRI and remained undetectable via PET imaging. The patient was able to come off all other treatments and returned to normal life and work activities, with complete remission for 7.5 months following therapy. This data, in concert with other similar, isolated reports of cellular therapies proving effective in hard-to-treat solid tumor indications suggests that CAR-T and other cellular therapies can indeed be effective in treating these types of cancer, but that it may be harder than the hematological indications, and changes may need to be made to adapt to the unique environment presented by solid tumors.
Addressing Solid Tumors. Building on the learnings from initial studies.
Data from the initial studies on solid tumors suggest differences and potential avenues of exploration. Eliminating solid tumors takes time, in the glioblastoma case cited above, the patient received 16 infusions over many months, continued dosing that may be required in order to allow the cellular therapy to destroy the tumor from the outside in. Unlike liquid tumors which present as individual cells circulating in the bloodstream, allowing all the tumor cells to be attacked by therapeutic T-cells at the same time, in solid tumors only the outermost layer is immediately accessible. Additionally, a hypoxic environment within the tumor may reduce the efficacy of the immune cells, and tumor microenvironmental factors such as checkpoint inhibition may serve to further reduce efficacy beyond the tumor boundary layer.
Targeted delivery is also critical to success in solid tumors. With blood-borne cancers, an intravenous infusion of the cellular therapy will deliver the therapeutic to the location of the disease. For solid tumors, a more targeted approach may be required to ensure sufficient concentrations of therapeutic cells at the site of the tumor. In the glioblastoma case cited above, this was made possible through intraventricular infusion, delivery of the drug directly into a fluid-filled cavity within the brain. This may go some way to explaining the effectiveness of the CAR-T cell therapy employed, as the location of the tumor within the brain, and behind the blood-brain barrier allowed for the buildup of higher concentrations of CAR-T cells over longer periods of time than might otherwise possible.
TCR-T: Increasing the number of targets
While CAR-T cell therapies, including those currently approved, can address cell surface antigens such as CD19 to effectively target and kill cancer cells in hematological indications, these cell surface antigens may not be sufficient to effectively address solid tumors. While cell surface antigens provide more easily addressed targets for a cell-based therapeutic, they represent only around 28% of all potential antigen targets with the other 72% being intracellular and beyond the reach of CAR-T. Given the other challenges involved in addressing solid tumors, it may prove necessary to expand beyond the readily accessible cell surface targets and increase the size of the playing field by including intercellular ligands.
T-cell receptor (TCR) T-cell therapy may well emerge as one such therapy for use against solid tumors utilizing recognition of peptide antigens generated from intracellular proteolysis and presented on the surface of the tumor cell via the peptide-major histocompatibility complex (pMHC). This gives TCR-T a window into the cell, allowing them to identify tumor cells based on the presence of tumor-associated antigens, cancer germline antigens, viral oncoproteins, and tumor-specific neoantigens - all of which are normally present only within the cell and made visible to the immune system via the class I and class II MHC complex.
In addition to the extended range of targets, TCR-T also shows higher sensitivity towards its target antigen than does CAR-T, with TCR T-cells having ten receptor structure subunits for every one in a CAR-T. This reduced sensitivity is one of the factors that has benefited CAR-T by reducing off-target effects, however, the increased sensitivity and reaction threshold of TCR-T may prove to be factors that enable them to succeed in the immunosuppressive microenvironment of a solid tumor.
Improving the killing power of cellular therapy for solid tumors
Other factors such as armoring which proved critical to the evolution of the first CAR-T cell therapies, in which co-stimulatory signaling factors such as CD28 and 4-1BB are included in the make-up of the re-engineered T-cell may prove critical in shielding engineered cells from the immunosuppressive environment inside a solid tumor and increasing the immune response. In the second and third-generation CAR-T cell therapies these cofactors were introduced to improve cell population expansion and T-cell persistence. In the next wave of engineered cellular therapeutics targeting solid tumors, cofactors are being explored to address the problems of the tumor microenvironment, improving the penetration, resistance, and killing power of these therapeutics.
Solid tumors present a much more challenging target than the blood cancers, and there is still much that we do not understand regarding these cancers and how to treat them, but the array of technologies currently being explored to address the problem is vast and we have already seen the first hints of success. The next few years promise to be an interesting time in the development of therapeutics for solid tumors as the technology evolves and we start to see the emergence of the first cellular therapeutics for the treatment of solid tumors.
Discovery Life Sciences and AllCells, Discovery Life Sciences’ dedicated cell and gene therapy division provide a range of products and services to support the development of cellular therapeutics. Visit the Discovery website to learn more about AllCells and Discovery's expanded capabilities.
National Cancer Institute. CAR-T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers. March 10, 2022. [online] Available at: cancer.gov [Accessed 4 May 2022].
Brown CE, et al. Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. New England Journal of Medicine 2016; 375:2561-2569 DOI: 10.1056/NEJMoa1610497
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