Immune cells that are genetically engineered with designer molecules to recognize and kill cancer cells may sound like an episode of science fiction, and for solid tumors, they used to be – until now. At the 2017 American Association for Cancer Research (AACR) Annual Meeting, City of Hope National Cancer Center reported on results from the first study ever to successfully use “Chimeric Antigen Receptor” (CAR) T cells to battle glioblastoma (brain cancer), as well as progress on a soon-to-enter-clinical-trials version for prostate cancer.
Imagine a world where rogue heroes go around battling bad guys to keep a community safe. They might even be specially trained in SWAT and sniper tactics, and are well-armed with Glock 22s and scope and laser-loaded Colt M4 Carbines. Not bad, so long as these heroes have the energy and ammunition to keep fighting. Except that in this tale, these good guys are trained to fight very obvious villains — like a crew of green alien invaders – not a stream of gangsters hiding in plain sight among the innocents. But what if we could genetically engineer our heroes with special bad guy-detection vision, such that even a terrorist with an inconspicuous guise could be spotted in the midst of any crowd, and taken down without harming anyone nearby? That’s the idea behind CAR T cells: upload a patient’s T cells, which are our bodies’ natural pathogen defense force, with specialized “enemy-recognition technology” – an engineered “CAR” gene that enables the T cell to pick a cancer cell out of the crowd — and kill it.
CAR T cells have previously made headlines for causing dramatic and long-term regressions in patients with certain types of leukemia and lymphoma. These CAR T cells were uploaded with a CAR that targets CD19, a gene specially expressed by B cells (an immune cell type that can become leukemia and lymphoma), which activates the CAR T cell to kill any cell encountered that expresses this target. Because of these successes, researchers have been racing to engineer CAR T cells that can target other tumor types. However, to limit side effects and maximize therapeutic potency, the CAR target selected needs to be specifically expressed by cancer cells and not cells that our bodies can’t get by without, which has proven to be more challenging than it sounds.
Towards a New Era in Cell Engineering for Immunotherapy
At the 2017 AACR meeting, Dr. Saul Priceman, a PCF Young Investigator and Assistant Research Professor at the City of Hope National Cancer Center, in Duarte, California, presented exciting evidence that CAR T cells can now be made to work against solid tumors, including glioblastoma and prostate cancer.
In a case report from a City of Hope clinical trial that was also recently published in the New England Journal of Medicine, a patient with glioblastoma was treated with CAR T cells targeting interleukin-13 receptor alpha 2 (IL13Rα2), which is expressed by glioblastoma cells. After exhausting all other treatment options, this patient received multiple injections of CAR T cells directly into his resected tumor space, which blocked any further growth of the brain tumor in that location for 45 days. When new metastases appeared in other parts of his brain and in his spine, the patient received 10 more injections of CAR T cells, this time into the ventricular system of his brain – a method that City of Hope researchers proved effective for broader distribution of CAR T cells throughout the central nervous system in mice — which caused complete regression of all brain and spinal tumors for 7.5 months in this patient. Although new tumors have since appeared, this patient remains alive over one and half years after initiating CAR T cell treatment – a remarkable feat for a patient who was otherwise expected to live for only another two to three months. This exciting clinical trial is ongoing at the City of Hope, which has treated 22 patients so far.
“This is a promising finding for the immunotherapy field, that we may be able to effectively treat aggressive brain cancers with CAR T cells,” said Priceman. “As exciting, is that a similar approach can be used to treat other previously intractable solid cancers, which has the potential to revolutionize treatment options for these patients.”
Dr. Priceman and colleagues are also developing CAR T cells to target prostate cancer, a project that is funded by the Prostate Cancer Foundation (PCF). The team has designed a CAR molecule that targets prostate stem cell antigen (PSCA), which is expressed in ~60% of primary prostate cancers and 80-100% of metastatic prostate cancers. PSCA is also expressed by other cancers, including pancreas and bladder, meaning that PSCA-CAR T cells may have applicability beyond prostate cancer.
In preclinical studies, Priceman and team demonstrated that PSCA-CAR T cells could specifically kill prostate cancer cells that express PSCA, and caused long-term regression of PSCA-expressing primary and metastatic prostate tumors in mice. PSCA-CAR T cells could also live for a long time in mice, which is important for long term efficacy – runaway tumor cells that have gone into hiding can be found by CAR T cells when they pop up later on and try to grow new tumors. This is one of the most unique and beneficial potential effects of immunotherapy – the production of a long-lived bad guy search-and-destroy team that continues to patrol a patient’s body until every last tumor cell is indeed, gone.
These achievements have not been without their challenges. CAR molecules are finicky things, and engineering the perfect CAR – one that can bind to its target with high specificity and strength, and activate the T cell the proper amount (too much could lead to peripheral damage while too little could be ineffective), is no small task. Priceman and colleagues have tested multiple iterations of their engineered PSCA-targeting CARs, and have finally landed on one that they believe is therapeutically optimal. The team is now going through institutional and federal regulatory procedures to prepare for clinical trials, with an activation date anticipated in early 2018.
“We are excited to initiate this trial, and while we believe this has the potential to change the landscape of therapies for metastatic prostate cancer, we also acknowledge the barriers to developing effective immunotherapy for this patient population, a challenge we are facing head-on in the laboratory,” said Priceman.
The 2017 AACR Annual Meeting was held from April 1-5, 2017, in Washington, D.C.
