A Practical Approach to CAR-T Therapies and Their Future

A Practical Approach to CAR-T Therapies and Their Future

The field of immuno-oncology has grown into one of the hottest topics in science, in terms of both potential and investment. Both major biotech firms and small startups are racing to stake their claim in the industry. While money is driving this push, the scientific advancements coming out of it really do seem to have the potential to change the face of oncological care. At the same time, it is necessary to remain cautious and avoid overly optimistic projections for the future. The potential is real, but expectations must be kept in check.

The Race toward Commercial CAR-T Therapies

One of the biggest players in immuno-oncology today is Juno Therapeutics, a biotech firm that is developing CAR (chimeric antigen receptor)-T therapies. However, Dr. Philip Greenberg, one of the founders of the firm, recently issued a reminder about the limitations of such therapies and the major hurdles that scientists continue to face as they refine technologies for the general market. Alongside Juno, other major names like Novartis and Kite Pharma are competing to identify the breakthrough therapy that will claim the CAR-T market. CAR-T therapy involves bioengineering cells in vitro to attack specific antigens found on the patient’s tumor. Then, the cells are reintroduced to the body.

Companies became interested in CAR-T therapies after some initial successes with early attempts at the therapy. However, these early promising results have not been repeated. In fact, the majority of cancer patients who have received CAR-T treatment have had relapses without long-term improvement. The treatment may also entail a number of serious side effects that could prove lethal in the weakened state of many patients with cancer.

The Immediate Hurdles that Researchers Face

Perhaps the most problematic side effect is cytokine release syndrome. T-cells release cytokines as they attack a tumor. In turn, the cytokines signal an inflammatory response. Because CAR-T therapy can result in the rapid, overwhelming release of cytokines, the body may react with nausea, fever, swelling, and fatigue. Neurotoxicity can also result from CAR-T treatments. This side effect causes brain swelling, memory loss, and hallucinations. These symptoms were observed in the three patients who died in the Phase II trial at Juno earlier this year.

Beyond the side effects, the other pressing issue with immuno-oncology is the extreme patient variability. A recent article appearing in Nature criticized the media for holding up success stories while ignoring the thousands of cases where the technology has not ultimately helped patients. Scientists and biotech leaders can also be misled by such media representation that inflates a few success stories unrealistically. While some might call this view pessimistic, a sober, realistic outlook is necessary to continue working toward an effective strategy.

A Glimpse at the Potential of CAR-T Treatments

Certain treatments have proven effective at treating certain types of patients. For example, a CAR-T study in Germany achieved remission rates up to 94 percent among patients with blood cancers. Many companies are now refocusing their efforts on identifying and overcoming the limitations of immuno-oncology to increase efficacy rates. One such company is ISA Pharmaceuticals, which recently found that more successful immunotherapies tend to target a tumor’s immunosuppressive mechanisms. Other companies can take advantage of this new understanding by combining treatments with checkpoint blockers or chemotherapy.

Some other interesting findings have also emerged recently. The Belgian company Celyad developed a CAR-T therapy directed at the modulation of the tumor microenvironment using a target that is present in 80 percent of cancers. Meanwhile, Stimunity, a company based in Paris, is developing a CAR-T treatment that triggers an immune response with a lower inflammatory profile—a particular benefit for patients with weak immune systems. Another French company, Cellectis, has worked to make CAR-T safer by creating a switch control system. The cells are inactive by default, but then activated when the immunosuppressant rapamycin is introduced into the system. This strategy was able to save the life of a one-year-old girl with leukemia last year.

A Realistic Approach to the Future of CAR-T Therapy

Physicians, patients, and the larger public need to understand that CAR-T therapies are not a panacea for cancer. While the treatment has a great deal of potential, much work needs to be done before patients can truly benefit from the approach. Tumors are still able to morph and avoid attack from T-cells—even ones that have been bioengineered through CAR-T therapy. In addition, cancer cells release potassium when they are destroyed, which in turn harms T-cells and prevents them from continuing their attack. Tumors also present inhibitory signals that can shut T-cells down.

Many of the challenges that researchers face are reminiscent of issues that arose with other treatment methods. The drug Avastin, for example, was designed to stop tumors from growing essential vasculature but then the cancer cells developed a new method of creating a blood supply. Similarly, molecular-targeted therapy was able to remove the molecules necessary for tumor growth and cell division, but then the tumors figured out different strategies for growth. Researchers need to remain realistic about the limitations of CAR-T in order to anticipate these issues and engineer a more effective therapy.

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