With cell therapy, clinicians are keenly aware of the point of no return. “Once my thumb hits the end of the syringe, the cells are in the body and we can’t get them back out,” says Stephan Grupp, director of cancer immunotherapy at the Children’s Hospital of Philadelphia, and a member of Eureka Therapeutics’ scientific advisory board. “We are with the patient on the rollercoaster until the ride is done.” Accordingly, there is a great deal of interest in developing the next-generation T cell therapy—built from genetically engineered T cells—that can deliver a response that is aggressive and controlled. This need will only become greater as oncologists go after solid tumors, which offer more challenging targets than blood cancers (see ‘Reaching Inside Tumor Cells’).

To tackle these challenging targets, Renier Brentjens, director of cellular therapeutics at the Memorial Sloan Kettering Cancer Center, and colleagues are developing what they call ‘armored’ CAR-T cells. These cells undergo additional reprogramming in order to churn out therapeutic proteins or signaling molecules that can reawaken immune cells in the vicinity of a tumor. “The armored CAR-T cell becomes kind of a ‘micro-pharmacy’,” explains Brentjens, who recently co-authored a Nature Biotechnology paper with Eureka concerning the company’s PD-1 inhibitor delivered by armored CAR-T cells. This approach is advantageous because some of these secreted molecules are too toxic for direct administration, but might be safe and effective when produced in moderate doses by T cells after navigating their way to the tumor. Their effectiveness against solid tumors might still be limited by the fact that they target a single antigen, which might not be universally expressed throughout the malignancy. But, if they are sufficiently effective at killing cancer cells, the immune system is likely to become exposed to additional antigens that enable it to engage in its own, additional, tumor eradication. Brentjens and colleagues are currently testing this approach in a clinical trial targeting solid tumors expressing a protein called MUC16.

However, the armored CAR-T cells still stimulate the same immune signals as conventional CAR-T treatment, and could elicit dangerous side effects, such as attacking healthy cells near the tumor site. “The armored CAR-T cells could be even more toxic than the regular T cells,” says Brentjens, “although we haven’t yet seen that to be the case.”

DOING WHAT COMES NATURALLY

Another innovative approach entails using T cells engineered to produce a more natural and restrained immune response. This is the aim of the ARTEMIS platform, developed by Eureka Therapeutics, which might prove safer for cell-based immunotherapy in blood and solid tumors.

In contrast to CARs, which are designed to simply recognize proteins on the surface of tumor cells, Eureka Therapeutics is engineering TCR-mimic (TCRm) antibodies on T cells that more closely follow the natural mechanism by which immune cells identify and respond to threats. The resulting cells can recognize fragments of cancer-specific antigens from the cellular interior, which are normally hidden from CAR-T cells, and deliver a more selective immune response. TCRm antibodies can be developed into drug candidates using Eureka’s ARTEMIS platform. Cells endowed with the ARTEMIS receptors generate only a subset of the immunological signals, or cytokines, released during CAR-T cell response, ideally stimulating a safer counterattack on the tumor.

In May 2018, Eureka announced its first-in-human clinical study data in which 21 patients with non-Hodgkin’s lymphoma received ET190L1 ARTEMIS T cells. Based on seeing a description of the results, Grupp says, “There’s no question that this very early stage data says that the cells can grow in a person and produce a clinical result. The cytokine profile and the toxicity associated with CRS are incredibly mild in the first handful of patients.”

BUILDING BETTER FUNCTIONS

Wendell Lim and colleagues at the University of California, San Francisco are exploring another approach, grounded in synthetic biology. “The goal of this field is not just to dissect biology, but to take components and ask how to build new functions,” explains Lim. After meeting CAR pioneer Carl June at a conference several years ago, Lim began looking into ways to more precisely control when and where immune cells are turned on or off. In an initial foray, his group developed a split CAR molecule that remains inactive until it encounters the appropriate pharmacological agent taken by the patient. “We showed that we can separate [one CAR into two] in a number of ways, and then use a drug-controlled domain to bring them back together,” says Lim.

Wendell Lim holds a model of a cellular receptor protein. Credit: Elena Zhokova

This conferred some external control over CAR-T cell activity, but Lim’s team has devised a more sophisticated approach in which cells are engineered to respond to various environmental cues by switching on different genes. For example, a T cell might be programmed to express an antibody on its surface that recognizes a tumor-associated protein; this binding event could then stimulate production of the actual therapeutic CAR molecule, which recognizes a second tumor protein and initiates the immune response. This approach could give these cells much-needed additional specificity, ensuring that they efficiently kill tumor cells without harming adjacent, healthy tissue expressing some of the same protein markers. “We liken it to face recognition — you can’t just have one modality for sensing something,” says Lim. “We find that it’s much more specific if we can sense solid tumors using a set of ‘eyes’ for a set of antigens.” This approach can also be used to engineer even more complex functionalities, and Lim’s technology has since been acquired for clinical development by CAR-T cell manufacturer, Gilead Sciences.

Fighting cancer is a daunting task, and oncologists are skeptical that risk can ever be taken completely out of the equation. “We’re going to have to be able to tolerate a certain amount of toxicity,” says Brentjens, “and we probably can’t make [treatments] completely painless.” However, he points out that this is also very much a field in its infancy, and that the future holds considerable potential for the development of tumor-killing T cells that act more like precision weapons than blunt instruments. “I imagine that 10 years from now we will be going into next-generation T cells that better optimize treatment and make it safer,” says Brentjens. “We have a Model T right now, but what we need is a Mustang.”

To learn about the challenges facing CAR-T cell therapies, visit our article.