In a study published in the journal Immunology, Southampton University researchers have shown that a new antibody that they have engineered is able to combine two different anticancer approaches: depleting regulatory T cells and activating killer T cells .
The costimulatory receptor 4-1BB is expressed on activated immune cells, including activated T cells. Antibodies targeting 4-1BB enhance the proliferation and survival of antigen-stimulated T cells in vitro and promote CD8 T cell-dependent anti-tumor immunity in pre-clinical cancer models. We found that T regulatory (Treg) cells infiltrating human or murine tumors expressed high amounts of 4-1BB. Intra-tumoral Treg cells were preferentially depleted by anti-4-1BB mAbs in vivo. Anti-4-1BB mAbs also promoted effector T cell agonism to promote tumor rejection. These distinct mechanisms were competitive and dependent on antibody isotype and FcgR availability. Administration of anti-4-1BB IgG2a, which preferentially depletes Treg cells, followed by either agonistic anti-4-1BB IgG1 or anti-PD-1 mAb augmented anti-tumor responses in multiple solid tumor models. An antibody engineered to optimize both FcgR-dependent Treg cell depleting capacity and FcgR-independent agonism delivered enhanced anti-tumor therapy. These insights into the effector mechanisms of anti-4-1BB mAbs lay the groundwork for translation into the clinic.
Regulatory T cells and killer T cells
T cells are immune cells produced by the thymus, a tiny organ located behind the collar bone. The job of killer T cells, also known as cytotoxic T cells, is to dispose of other cells that are infected, cancerous, or otherwise damaged; regulatory T cells, as their name suggests, modulate and downregulate the immune response, as their function is primarily immunosuppressive, which is to prevent the immune system from attacking its own body and thus prevent autoimmune diseases.
A high level of regulatory T cells within a tumor may dampen the body’s immune response against it, leading to worse patient outcomes, though this seems to depend somewhat on the type of tumor and its location within the body; depleting regulatory T cells is thus an immunotherapeutic avenue, as is stimulating killer T cells. However, while immunotherapy is in general a very promising anticancer approach, it normally works well only in relatively few patients; thus, finding ways to improve its efficacy is a primary objective of cancer research.
The authors of the study focused their efforts on a receptor called 4-1BB, which, as they found out, is expressed by both regulatory T cells and killer T cells, although the former express much higher levels of the receptor than the latter. It’s possible to deplete regulatory T cells in tumors by targeting 4-1BB with specific antibodies, which boosts anti-tumor immunity in in-vitro and preclinical settings, but this procedure fails to simultaneously stimulate killer T cells; in other words, anti-4-1BB antibodies remove the dampener of the immune response, but they don’t elicit a stronger one.
However, after a decade-long joint effort with BioInvent International, the researchers managed to design and engineer a new type of anti-4-1BB antibodies called anti-4-1BB mAbs, which combine both approaches into one, depleting regulatory T cells and activating killer T cells at the same time.
The technique proved very effective in several tumor models in the laboratory; the researchers think that it may be applicable to ovarian and skin cancer and that, in the future, it may be adapted to extend its applicability to yet other cancer types.
According to Prof. Stephen Beers, one of the lead authors of the study, this research helped elucidate some of the reasons why therapies targeting 4-1BB have failed to make it to the clinic before, and this demonstrated ability to combine the two immunotherapeutic approaches may pave the way to more effective treatments against cancer.
 Buchan, S. L., Dou, L., Remer, M., Booth, S. G., Dunn, S. N., Lai, C., … Beers, S. A. (2018). Antibodies to Costimulatory Receptor 4-1BB Enhance Anti-tumor Immunity via T Regulatory Cell Depletion and Promotion of CD8 T Cell Effector Function. Immunity.