Stimulating CD27 to quantitatively and qualitatively shape adaptive immunity to cancer

Abstract

The capacity of the immune system to recognize and respond to tumors has been appreciated for over 100 years. However, clinical success has largely depended on the elucidation of the positive and negative regulators of effector cells after activation via the antigen cell receptor. On the one hand, effector cells upregulate checkpoint molecules that are thought to play a role in limiting immunopathology. On the other, second and third waves of costimulation are often required to promote the expansion, survival and differentiation of effector cells. While it is clear that the immune system can be unleashed by blocking checkpoint molecules, this approach is most effective when preexisting responses exist in patients. Thus, coordinating checkpoint blockade with costimulation could potentially expand the patient population that receives benefit from cancer immunotherapy. This review will discuss how the costimulatory molecule CD27 sculpts immunity and preclinical/clinical data indicating its potential for cancer immunotherapy and its clinical translation.

A Single-Chain-Based Hexavalent CD27 Agonist Enhances T Cell Activation and Induces Anti-Tumor Immunity

“…In addition, this benchmark antibody failed to induce CD27-mediated signaling activity at a wide range of concentrations. These results support the concept that bivalent compounds, like antibodies, have even more trouble clustering a sufficient number of receptors to transmit a productive signal ( 8 , 10 , 13 , 14 , 22 , 30 ). The data also support our previous findings with HERA-TRAIL suggesting that TNFRSF receptor clustering, best achieved by higher order structures based on the natural ligand, is required for full induction of down-stream signaling and function ( 14 ).…”

“…Through ADCC and ADCP, FcγR binding leads to the elimination of CD27 expressing T cells, an unnecessary side effect associated with antibody-based therapy. In fact, reduced numbers of CD4+ T cells and Treg cells were observed in both pre-clinical and Phase I clinical trials of this benchmark anti-CD27 antibody ( 10 , 36 ). While the reduction in effector T cell numbers suggests further limitations of efficacy, the elimination of Treg cells is especially problematic as there are many dangers associated with Treg cell depletion as a therapeutic strategy ( 37 ).…”

“…This point is critical since the majority of T cells express CD27 and could, therefore, respond to HERA-CD27L treatment. This also makes HERA-CD27L particularly suitable for combination therapy with strategies that provide additional antigen-specific immune cells, such as vaccination and adoptive cellular transfer ( 10 , 20 , 21 ).…”

Engineered cells for costimulatory enhancement combined with IL-21 enhance the generation of PD-1-disrupted CTLs for adoptive immunotherapy

“…After extensive ex vivo expansion, loss of the expression of the critical co-stimulatory molecule, CD28, as well as the loss of CD27, another important T-cell co-stimulatory molecule, have been reported [52]. After expansion, CD27 stimulation can both increase effector cell expansion and survival and enhance the development of memory CD8+ T cells [53]. CD28 is critical for regulatory T cell survival and the maintenance of immune homeostasis [54].…”

Trial Watch: Immunostimulatory monoclonal antibodies for oncological indications

“…42,49,[61][62][63][64][65][66] One of these approaches is based on mAbs or fusion proteins that operate as agonists for co-stimulatory receptors expressed by CTLs, NK cells, CD4 C helper T cells, or APCs (Table 1). [67][68][69][70][71] The most relevant receptors in this setting are CD27, [72][73][74] CD28, [75][76][77] CD40, [78][79][80][81][82] TNF receptor superfamily, member 4 (TNFRSF4; best known as OX40), [83][84][85] TNF receptor superfamily member 9 (TNFRSF9; best known as CD137 or 4-1BB), [86][87][88][89] TNF receptor superfamily member 18 (TNFRSF18; best known as GITR), [90][91][92] and inducible T-cell costimulatory (ICOS). [93][94][95][96][97] The natural ligand for CD27 is CD70, 74,[98][99][100][101][102] CD28 is activated by CD80 and CD86 (hence sharing ligand specificity with CTL...…”