Phase 1 trial tests “weaponized” CAR-T cell therapy to improve lymphoma response

It is a clinical trial led by Dr. Carl June with extraordinary results of efficacy in patients with lymphoma previously refractory to CAR immunotherapy in which more than half of the previously refractory patients achieve a complete response of their lymphoma.  

The molecular trick consists of introducing into the lymphocytes, together with the CAR gene, another gene coding for an immunostimulant substance called interleukin-18. The CARs thus constructed to co-express cytokines are called armed CARs, and have greater therapeutic potency. This concept has been tested preclinically and clinically with other cytokines, but with more modest clinical results. Our group published in preclinical models the mechanisms by which we observed that adoptive cell therapy armed with interleukin-18 is more potent through the lymphocytes' own self-stimulation, which allows them to better migrate to tumor tissue and adapt to the metabolic stress present there. 

The observations in patient samples of persistence of CARs demonstrating interleukin-18 activity are extraordinarily interesting. From a safety standpoint, adverse effects are very comparable to those of conventional CAR therapy and appear manageable. This strategy seems suitable for treating refractory patients and all indications are that it will soon be tested as the first CAR treatment in patients with B lymphomas refractory to conventional therapies. 

The work is of excellent quality and proposes a new structure that, beyond allowing the recovery of therapeutic options for patients who relapse to a first CAR-T configuration, suggests that these first CAR-Ts can be recovered if combined with a cytokine.  

The work suggests, but does not prove, that adding this double structure (CAR+IL18) could be more effective than the first CAR-T, which is an approved product. However, for the moment what it shows is that it can be a subsequent proposal when the first one fails and suggests that this cytokine that “reinforces” the cellular function can prevent the CAR-T proposal from failing to achieve its objective, which is to eliminate the tumor because it lacks this reinforcement by the microenvironment. 

In any case, the proposal itself fits with the existing evidence, implying that new comparative clinical trials with the approved products may improve the efficacy with respect to the already approved CAR-Ts.

The study is not particularly different from other phase 1 clinical trials, but it stands out for the striking efficacy results and for being the first clinical trial with successful results with new generation CAR-T therapy on an ultrafast platform.   

It is a phase 1 trial very limited in the number of cases, but with surprising results for the great efficacy of the therapy in patients who have relapsed to a CAR-T treatment. It is the first clinical study to be performed with fourth-generation CAR-T with successful results. In addition, toxicity is similar to that of second-generation CAR-Ts. 

The main limitation is that the data have to be confirmed in larger studies.