Genetic Engineering in the Press by GEG

Among the immunotherapies available, the use of CAR-T cells is proving extremely effective against certain blood cancers, but only in half of patients. One of the main reasons for this is the premature dysfunction of these immune cells, which have been artificially modified in vitro. A research team has discovered how to prolong the functionality of CAR-T cells. By inhibiting reductive carboxylation, the team has succeeded in creating CAR-T cells with enhanced immune memory, capable of fighting tumor cells for much longer. These are very promising results, to be read in the journal Nature. Without reductive carboxylation, CAR-T cells do not differentiate as much and retain their anti-tumor function for longer. They even tend to transform into memory T lymphocytes, a type of immune cell that retains a memory of the tumour elements that need to be attacked. The inhibitor used to block reductive carboxylation is a drug already approved for the treatment of certain cancers. It is therefore possible to reposition it in order to extend its use and produce more powerful CART cells in vitro. Of course, its efficacy and safety need to be tested in clinical trials

A type II variation application seeking approval of the ciltacabtagen autoleucel (Carvykti, cilta-cel) in adult patients with relapsed multiple myeloma refractory to lenalidomide has been submitted to the European Medicines Agency. The application is based on the results of the phase 3 CARTITUDE-4 trial (NCT04181827), with data showing that CAR T-cell therapy reduces the risk of disease progression or death compared with pomalidomide (Pomalyst), bortezomib (Velcade), and dexamethasone (PVd) or daratumumab (Darzalex), pomalidomide and dexamethasone (DPd) in people with relapsed or refractory disease who have received 1 to 3 prior lines of therapy. Median progression-free survival (PFS) has not yet been achieved with cilta-cel versus 12 months with the control regimen. In addition, PFS rates at 12 months were 76% in the experimental group and 49% in the control group. CAR T-cell therapy elicited an overall response rate of 88% versus 67% with control. Notably, 73% of patients who received cilta-cel had a complete response to treatment versus 22% who received control. Data will be shared in a special session at the next ASCO annual meeting.

Currently, no CAR T agents have been approved by the FDA for the treatment of solid malignancies. Several other Phase 1 clinical trials are underway to evaluate the safety and efficacy of CAR T agents, as monotherapy or in combination, in solid malignancies such as glioblastoma, as well as in other cancers. Seeking to replicate the impressive results of CAR-T cell therapies seen in patients with hematological malignancies, researchers launched the BASECAMP-1 trial (NCT04981119) in the hope of identifying patients with advanced solid tumors who would be suitable candidates for treatment in the phase 1/2 EVEREST trial (NCT05736731) evaluating the A2B530 agent. This agent was designed using the novel Tmod logical T cell therapy platform. Tmod agents contain an activating receptor, either a CAR or a T cell receptor, which recognizes an antigen on the surface of tumor cells, specifically CEA in the case of A2B530, and an inhibitory receptor, or blocker, based on the LIR-1 protein, designed to enhance the tumor specificity of the agent. The blocking part of A2B530 exploits the loss of heterozygosity of the HLA-A*02 antigen, one of the most common alleles observed in tumor cells from a US population, to prevent the CAR from affecting healthy tissues.