Immunotherapy in solid tumors: Potential for an entire market segment to be redistributed

Driven by the success of CD3 T cell engagers (CD3 TcE) in hematological cancers,  the pharmaceutical industry has made major investments to build portfolios for the treatment of cancer based on bispecific antibodies commonly known as T-cell engagers or “BiTE” molecules. These molecules have 2 modules: a CD3-binding component to artificially activate αβ-T cells and a tumor antigen binder to focus the primarily nonspecific activity of T cells on tumor cells. However, the effect of these drugs seems rather limited in the immunosuppressive milieu of solid tumors (Fucà et al., ESMO Open 2021 Feb;6(1):100046). In addition to regulatory T cells, there is a plethora of immunosuppressive factors known as “immune checkpoints” (ICs) that inhibit T cell activity in the tumor and prevent them from responding to artificial stimulation by CD3.
A normally useful strategy to combat tumor resistance mechanisms is drug combinations. In this case, however, the value of such a strategy seems questionable: The heterogeneity of immune suppressive factors in solid tumors makes it difficult to identify a single combination partner. Moreover, trials combining more than one of the currently approved immune checkpoint drugs lead to a steap increase in severe to life-threatening side effects (Barbari et al., Int J Mol Sci 2020, 21: 5009). In short, trying to rescue CD3-based T-cell engagers by combining them with immune checkpoint inhibitors carries considerable risks that should be taken into account in practice.

After more than 1000 patients with solid tumors treated and only 3% reportedly showing objective responses, it seems prudent to reconsider this approach and to replace it in the near future. Evobright wants to offer our pharma partners an attractive opportunity to de-risk their previous investments in CD3-based compounds by adding an additional opportunity to their development portfolio for solid tumors.