The "Trojan Horse" approach to tumor immunotherapy: targeting the tumor microenvironment

Abstract

Most anticancer therapies including immunotherapies are given systemically; yet therapies given directly into tumors may be more effective, particularly those that overcome natural suppressive factors in the tumor microenvironment. The "Trojan Horse" approach of intratumoural delivery aims to promote immune-mediated destruction by inducing microenvironmental changes within the tumour at the same time as avoiding the systemic toxicity that is often associated with more "full frontal" treatments such as transfer of large numbers of laboratory-expanded tumor-specific cytotoxic T lymphocytes or large intravenous doses of cytokine. Numerous studies have demonstrated that intratumoural therapy has the capacity to minimizing local suppression, inducing sufficient "dangerous" tumor cell death to cross-prime strong immune responses, and rending tumor blood vessels amenable to immune cell traffic to induce effector cell changes in secondary lymphoid organs. However, the key to its success is the design of a sound rational approach based on evidence. There is compelling preclinical data for local immunotherapy approaches in tumor immunology. This review summarises how immune events within a tumour can be modified by local approaches, how this can affect systemic antitumor immunity such that distal sites are attacked, and what approaches have been proven most successful so far in animals and patients.

Figure 1

Conceptual illustration of the “Trojan horse” approach to tumor immunotherapy. An immune modulator is delivered directly into a portion of the tumor. That results in inflammation plus “dangerous death”. This results in mobilization of an “army” of tumor specific T cells which then attack the area of the tumor injected plus uninjected areas of tumor, especially if addition agents are provided which promote access of these T cells into these areas and/or local stimulation, for example, agonistic anti-CD40 antibodies.

Figure 2

Animal study showing how intratumoral therapy induces local regression plus distal regression of uninjected tumor. Intratumoural IL-2 + anti-CD40 is an effective combination against local tumour and untreated distal tumours. C57Bl/6J mice were injected s.c. with 5 × 10⁵ AE17 tumour cells into the left flank and 5 × 10⁵ AE17 cell into the right flank on day 0 and left to develop into large tumours before treatment began. The i.t. treatments were delivered into one tumour indicated by arrows (treated tumour: a), whilst the second (distal) tumour was left untreated (b). Data from 1 experiment (5 or 6 mice/group) is shown as mean ± SEM. Treated mice were compared to PBS-treated controls mice; **P < 0.01, ***P < 0.001 (from Jackaman et al., 2008. International Immunology) [29].

Figure 3

Induction of local and widespread antitumor reactivity with continuous cytokine infusion into tumors. Recombinant human GM-CSF was administered continuously into the tumor of a patient with pleural mesothelioma using a pump attached to an intratumoral cathers via a subcutaneous port (a) Tumor biopsies (H&E) taken before (b) and after (c) 8 weeks of continuous intratumoral infusion of GM-CSF. Shown is a marked influx of immune cells into uninfused tumor following the therapy. This patient exhibited a generalized partial response (>50% diffuse tumor reduction).

Figure 4

Illustration of the ways in which “Trojan Horse” approaches immunotherapy might be effective. Tumors that are destroyed by local therapy (1) deliver tumor antigens into the draining lymph node (2), that is, the tumor acting as its own vaccine. This cross-primes an antitumor T cell response which, when the tumor vasculature is modified to encourage entry into the tumor (3), results in the accumulation of effector T cells in the tumor. Once local suppressive defenses are overcome (4) and a milieu that is conducive to local effector events is established (5), tumor destruction can result.