Stepping On the Gas with CAR T-Cell Therapy
Immune Suppression for Better Immune Recruitment?
Background
Humanized mouse models? Engineered chimeric T cells? Metastatic castration-resistant prostate cancer? Sounds like a low-budget Halloween film (just like our last foray into immunology), but these terms are all found within a study by John Murad and his colleagues which describes a way to enhance cancer therapy efficacy. To understand how these concepts all fit together, we need to cover a bit of background information first.
Chimeric antigen receptor (CAR) T cell therapy is a cancer treatment in which scientists take a sample of inactivated T cells, introduce an engineered T cell receptor gene (encoding the CAR), and culture millions of new, active cells before re-introducing them into the patient. The CAR can be engineered to target nearly any tumor surface protein, and the cultured cells can get to work as soon as they enter the body. This therapy is currently limited to non-solid cancers (like leukemias and lymphomas), as CAR T-cell therapy has proven largely ineffective in treating solid tumors, which brings us to the cancer type studied in this paper.
Metastatic castration-resistant prostate cancer (mCRPC) is a solid tumor that expresses the prostate stem cell antigen (PSCA) protein on its surface. PSCA is expressed in low levels in multiple organ systems like the pancreas, bladder, and stomach but is present in very high concentrations on mCRPC cell surfaces. Like many other solid tumors, its tumor microenvironment (TME) is very hostile to the immune system. Immune cells are excluded from entering the tumor, and cells that do manage to infiltrate it are shut off by tumor signals. This allows the tumors to not only evade the immune system while growing and spreading but also to resist immune therapies like CAR T-cell therapy.
Summary: Inhibiting the Immune System to Boost Its Efficacy?
As mentioned above, PSCA is expressed in tissues throughout the human body. In theory, this makes it risky to introduce CAR T-cells targeting PSCA. Fortunately, mice have nearly the same distribution of PSCA throughout their tissues as humans, so the researchers generated a mouse mutant wherein the human PSCA gene was linked with the mouse PSCA promoter. This produced a mouse with both human PSCA and accurate distribution, giving them a testable model to assess side effects for anti-PSCA CAR T-cell therapy. When they performed their trial with mCRPC tumor (PSCA+ tumors), they found that PSCA-CAR T-cells selectively attacked tumor cells without significant side effects but with little efficacy. Fascinatingly, the researchers found that the therapy worked better in mice with non-functioning immune systems, suggesting that the individual’s own immune system contributes to the therapy resistant TME.
To investigate this, the researchers next tried treating mice with cyclophosphamide (Cy) before administering the PSCA-CAR T-cell therapy. Cy is a common, tried-and-true immune system repressor that is used to avoid organ transplant rejection. This pre-treatment is supposed to briefly “clear” the immune system, creating a treatment window to enhance the efficacy of the CAR T-cell therapy.
This produced astonishing results. Mice with both PSCA-CAR T therapy and just one 100mg/kg dose of Cy displayed complete tumor regressions and improved overall survival rates. Other combinations (Cy or PSCA-CAR T cells alone) yielded just brief tumor regressions and no significant survival benefits. Other tests confirmed that it was only the combination of PSCA-specific CAR T-cells and Cy pre-treatment that shut off tumor resistance. No observable side effects were produced, further supporting the safety of this treatment.
To determine exactly why Cy pre-treatment assisted PSCA-CAR T-cell therapy, the researchers studied biopsies taken from tumors before and after treatment combinations. Consistent with their model, Cy promoted invasion of T-cells into the tumor. If PSCA-CAR T-cells were administered, this effect was amplified (up to 10x more infiltration). T-cell invasion is very important for the efficacy of CAR T-cell therapy, as the T-cells have to physically reach their target cells to destroy them. RNA analysis confirmed that Cy produces an immune-friendly environment within the tumor, encouraging T cell migration and activation, increased antigen presentation, and broader immune cell recruitment.
To further test their therapy, the researchers measured its long-term protection against tumors and its efficacy against bone metastases (traditionally considered incurable). Only PSCA-CAR T-cell therapy combined with Cy pre-treatment produced significant effects in either of these trials, yielding a 50% curative response in mouse models and general anti-tumor responses in most mice. When the same tumor line was re-introduced after the combination therapy, 80% of the mice showed a strong immune response similar to graft rejection. This suggests that the combination treatment produces a potent, long-lasting anti-tumor immune response.
To wrap things up, the researchers tried their therapy against a different type of cancer. Metastatic pancreatic cancer is one of the most aggressive cancers out there, partly due to its ability to exclude T cells. Fortunately, it also overexpresses PSCA on its surface, so the researchers tried their treatment against this cancer in a mouse model. Once again, their combination arm produced the most encouraging results, with curative responses and improved survival rates observed in over 60% of mice.
CAR T-cell therapy remains a powerful tool in our arsenal of anti-cancer treatments, but it has been met with significant challenges along the way. This article represents a breakthrough in our understanding of anti-tumor treatment, shedding some valuable insight on the mysterious nature of the immunosuppressive tumor microenvironment. As targeted therapies continue to improve, one can dream of a future treatment routine that doesn’t burden patients with the brutal side effects of some modern therapies. With such ingenious research paving the way forward, the future of cancer treatments appears bright.
Further Readin
CAR T-Cell Therapy Q+A: Demarco C. 2018. 9 things to know about CAR T-cell therapy. MD Anderson. https://www.mdanderson.org/cancerwise/car-t-cell-therapy--9-things-to-know.h00-159221778.html
Tumor-Associated Macrophages: Noy R, Pollard J. Nov 2014. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41(1):49–61. https://doi.org/10.1016/j.immuni.2014.06.010.
Bone Metastasis: Coughlin et al. 2017. Bone: a fertile soil for cancer metastasis. Curr Drug Targets (18)11:1281–1295. 10.2174/1389450117666161226121650.
