Why so much excitement about CAR-T cells?

July 12, 2017, marked a historic day for medicine and for the US Food and Drug Administration (FDA) when an expert advisory committee to the FDA unanimously endorsed the first ever genetically engineered, cell-based therapy for use in patients. If accepted by FDA regulators for approval to treat patients, the therapy, called CAR-T CTL019 (tisagenlecleucel) and produced by Novartis, will be for patients with a blood cancer called B cell acute lymphoblastic leukemia, aged 3 to 25, who have relapsed or resisted other treatments. How this cell-based therapy compares to current cancer treatments is what makes it so unique. https://www.novartis.com/news/media-releases/novartis-car-t-cell-therapy-ctl019-unanimously-10-0-recommended-approval-fda

 
In contrast to the currently approved therapies for B cell acute lymphoblastic leukemia, like chemotherapy and bone marrow transplant, CAR-T CTL019 is an entirely different beast developed based on the pioneering work of Carl June at University of Pennsylvania. First off, the therapy is generated from a specialized kind of the patient’s own white blood cells, called T cells. These are the same types of cells that are the target of approved checkpoint blockade therapies like nivolumab, pembrolizumab and ipilimumab, since under the right conditions they can deliver a lethal attack to tumors. Unlike these other immunotherapies, however, CAR-T CTL019 are generated by first removing T cells—on the order of millions—from the patient. Next, the cells are grown in culture and a virus is used to genetically engineer the cells to express something called a CAR—a chimeric antigen receptor. What this CAR does is allow the T cells to recognize a protein called CD19 expressed by all B cells in the body, including the tumor cells. Finally, the cells are re-infused into patients, where they can mount a ferocious attack (more on that later). Initially, the entire process took months but Novartis now says it has optimized the process so that it takes 22 days from cell removal to reinfusion. An off-the-shelf product, this is not. But, a major step forward for patients? Yes!

So why go through this arduous process to make such a customized treatment? Because of the extremely impressive impact the therapy can have on patients. Of 63 patients treated over the course of 16 months, 52 (83%) went into remission. Overall survival data at one year was 79%. Although some patients later relapsed, several patients continue to remain cancer-free. In fact, the first patient to ever receive the therapy six years ago was present at the advisory committee meeting to testify about the impact of the therapy and witness the historic event.

Given these impressive results, unanimous endorsement by the advisory committee for CAR-T CTL019 should have been a sure thing, right? The answer to this question is a bit more complicated (remember the ‘more on that later’?). First of all, similar to other approved immunotherapies, patients treated with CAR-T CTL019 often experience serious toxicities. One of the most severe, and one which has killed some patients, is something called cytokine-release-syndrome. As part of the process of killing tumors, the CAR-T cells release a host of inflammatory factors into the body, causing a range of symptoms that include a high fever, low blood pressure and multi-organ shut-down. Fortunately, these symptoms can be managed if patients are carefully monitored and treated as soon as symptoms arise.

Another concern is the manufacturing process itself. Once the cells are removed from patients, they must be frozen, sent to Novartis’ manufacturing facilities, cultured and engineered, and finally re-frozen and shipped back to the hospital where they are thawed and given back to the patients. In the past, patients have died while waiting for the cells to be ready. Also, given the complexities in administering the therapy, Novartis plans to limit its use to only 30-35 medical centers where staff are highly trained to deliver the therapy and manage patient symptoms. So this means accessibility to the treatment will be limited, at least early on.

Finally, the long-term effects of the therapy remain unknown. Will the cells stick around long term in some patients and cause secondary cancers or other unknown diseases? While multiple patients who received the therapy several years ago remain cancer-free today and without any apparent, long-term adverse effects, patients receiving the therapy will enter into a registry where doctors will monitor them for 15 years to determine the longer-term effects of the therapy.

Another company, Kite Pharma, is also engaged in developing a similar treatment. And in a show of camaraderie, Kite’s CEO said in a blog post “Today is not about business or competition. Today, we are not rivals. Today is about advancing an exciting technology that has the potential to transform cancer treatment.” http://www.kitepharma.com/2017/07/car-t-in-the-spotlight/

What does this all mean for melanoma patients? For the time being, CAR-T CD019 will not affect how melanoma is treated since the molecule targeted by the therapy is only expressed by the immune-system’s B cells, which is the cell affected by type B-cell acute lymphoblastic leukemia. However, should the FDA ultimately decide to approve CAR-T CD019 it will likely open the door to future cell-based therapy approvals. For now, CAR-T CD019 is a fairly unique case since the molecule it targets is only expressed by B cells, and these cells are largely expendable. No similar target exists for melanoma yet, but researchers could discover such a target and clinical trials using other types of cell-based therapies have shown great promise in treating late-stage melanoma.

So what’s next? For now, we wait until FDA regulators make their final decision. But it certainly looks like the door may be opening for entirely new types of cancer therapy in the future.