ImmTAC-redirected tumour cell killing induces and potentiates antigen cross-presentation by dendritic cells

Abstract

Antigen cross-presentation by dendritic cells (DCs) is thought to play a critical role in driving a polyclonal and durable T cell response against cancer. It follows, therefore, that the capacity of emerging immunotherapeutic agents to orchestrate tumour eradication may depend on their ability to induce antigen cross-presentation. ImmTACs [immune-mobilising monoclonal TCRs (T cell receptors) against cancer] are a new class of soluble bi-specific anti-cancer agents that combine pico-molar affinity TCR-based antigen recognition with T cell activation via a CD3-specific antibody fragment. ImmTACs specifically recognise human leucocyte antigen (HLA)-restricted tumour-associated antigens, presented by cancer cells, leading to T cell redirection and a potent anti-tumour response. Using an ImmTAC specific for a HLA-A*02-restricted peptide derived from the melanoma antigen gp100 (termed IMCgp100), we here observe that ImmTAC-driven melanoma-cell death leads to cross-presentation of melanoma antigens by DCs. These, in turn, can activate both melanoma-specific T cells and polyclonal T cells redirected by IMCgp100. Moreover, activation of melanoma-specific T cells by cross-presenting DCs is enhanced in the presence of IMCgp100; a feature that serves to increase the prospect of breaking tolerance in the tumour microenvironment. The mechanism of DC cross-presentation occurs via 'cross-dressing' which involves the rapid and direct capture by DCs of membrane fragments from dying tumour cells. DC cross-presentation of gp100-peptide-HLA complexes was visualised and quantified using a fluorescently labelled soluble TCR. These data demonstrate how ImmTACs engage with the innate and adaptive components of the immune system enhancing the prospect of mediating an effective and durable anti-tumour response in patients.

Elimination of Latently HIV-infected Cells from Antiretroviral Therapy-suppressed Subjects by Engineered Immune-mobilizing T-cell Receptors

“…20,25 ImmTACs have shown promise in vitro and in early clinical trials in melanoma and a similar technology employing antibody-mediated redirection led to development of bispecific T-cell engagers such as blinatumomab, which was recently licensed for of the treatment of certain leukemia. 26,27,28,29,30,31 …”

New Strategies in Melanoma: Entering the Era of Combinatorial Therapy

“…Furthermore, it appeared that the patients most likely to have an improvement in survival, assessed in a subset analysis, were those with unresectable stage III disease (HR, 0.57; P < 0.001). A second example of next-generation vaccination strategies is IMCgp100, a bifunctional molecule that targets the gp100 280-286 peptide presented by HLA-A2 on one end and recruits T cells via a low-affinity anti-CD3 component on the other end (52). The initial data from the phase I, doseescalation trial was presented and was associated with definitive tumor responses in at least 2 of the first 10 patients (53).…”

Antibody therapies for melanoma: New and emerging opportunities to activate immunity (Review)

“…Numerous studies by us and others point towards consideration of antibodies of classes such as IgA or IgE with tissue immune surveillance functions that may be well-suited to the phenotypes of tumour-resident effector cells (101–107). Future studies may also provide further insights into the pathways associated with immune cell activation and re-direction in patient circulation and tumour microenvironments (11,14,15,62,108).…”