SAVALnet – Science and Medicine

He glioblastoma This is the most difficult of primary brain tumors, due to its aggressive nature and the limited effectiveness of available treatments, which include maximum safety surgical resection, radiation therapy, and alkylating chemotherapy. Most patients die within one year of diagnosis, highlighting the urgent need for innovative therapeutic strategies. Based on this, Choi and collaborators at Massachusetts General Hospital and Harvard Medical School (USA) reported in an interim analysis the results of treating three patients with Chimeric antigen receptor T-cell therapy (CAR-T).

This technology has changed the therapeutic approach to combating hematological cancers. It uses a patient’s own T cells, genetically equipping them with chimeric antigen receptors (CARs) that allow them to recognize and bind to an antigen on a cancer cell and then eliminate it.

Therapy approved by the Food and Drug Administration (FDA), including tisagenlecleucel And axicabtagene ciloleucel, demonstrated high efficacy against acute lymphoblastic leukemia and diffuse large B-cell lymphoma. However, generalization of this beneficial effect to solid tumors such as glioblastoma is difficult due to the tumor microenvironment, cellular and genetic heterogeneity, and immunosuppressive elements.

Some tumors contain unique proteins specific to this pathology. For glioblastoma, a specific protein epidermal growth factor receptor variant III (EGFRvIII)truncated and constitutively active version REFR. However, clinical trials have shown that tumors targeted by T cells engineered to recognize EGFRvIII can develop resistance, especially those with high expression of nonvariant EGFR.

In addition to transducing autologous T cells with DNA encoding CAR, the authors also included a sequence for the synthesis bispecific antibody which recognizes EGFR (expressed by tumors) and CD3 (expressed by T cells). They called this system TEAM-E, a type of bispecific activator. It is secreted by T cells and is similar to a tether in that it holds these cells very close to the glioblastoma (Figure 1). T cell CARv3-TEAM-E targets two antigens (EGFR and EGFRvIII) and represents an approach that can overcome the heterogeneity and complex pathological characteristics of this cancer type. Another advantage is the local delivery of elements secreted by T cells into the tumor microenvironment, which minimizes systemic toxic effects.

Figure 1: Preparation and administration of CARv3-TEAM-E T cells.

Choi et al. observed marked radiographic tumor regression shortly after a single infusion of CARv3-TEAM-E T cells. This effect occurred in all three patients, but the response was transient in two and persistent in the third. The safety profile was significant, with manageable adverse events and no dose-limiting toxic effects. The prompt response supports further research on cell therapy for the treatment of advanced pathology by intraventricular administration. Although such a procedure involves surgery (installation of an injection port called an Ommaya reservoir), it would likely allow direct delivery of the drug to the tumor and avoid the systemic activity that may result from peripheral administration, especially if CAR-Ts are used. They target molecules that are expressed outside the central nervous system. Given the destructive nature of glioblastoma, this invasive route of administration is justified.

The transient response in two of three patients enrolled highlights the need for further studies to improve and prolong the effectiveness of this promising therapy. Extending the lifespan of CAR-T cells and integrating combination therapies are necessary to counteract the immunosuppressive nature of the tumor microenvironment. Indeed, glioblastomas have highly immunosuppressive myeloid compartments that promote immune evasion and tumor growth. It is also important to overcome the problem of heterogeneity brain tumors.

The field is turning to multi-target CAR-T cell strategies, as exemplified by a pioneering clinical trial based on this therapy against four different antigens to treat children and young adults with brain cancer

in Seattle. Regarding CARv3-TEAM-E T cells in the treatment of glioblastoma, the results presented by Choi et al are cautiously optimistic. However, only by increasing the sample size will it be possible to evaluate the effect and scalability of this therapy.

Bibliographic source

CAR T-cell therapy for glioblastoma

Misty R. Jenkins, PhD, and Katherine J. Drummond, MD, MB, BS

University of Melbourne, Melbourne, Australia

N Engl J Med 2024; 390:1329-1332