Long-lived and transferable tumor immunity in mice after targeted interleukin-2 therapy.

Abstract

A major goal of tumor immunotherapy is the induction of tumor-specific T cell responses that are effective in eradicating disseminated tumor, as well as mounting a persistent tumor-protective immunity. We demonstrate here that a genetically engineered fusion protein consisting of human/ mouse chimeric anti-ganglioside GD 2 antibody and human interleukin-2 is able to induce eradication of established B78-D14 melanoma metastases in immunocompetent syngeneic C57BL/6J mice. This therapeutic effect is mediated by host immune cells, particularly CD8ϩ T cells and is associated with the induction of a long-lived immunity preventing tumor growth in the majority of animals when challenged up to four months later with B78-D14 cells. This effect was tumor-specific, since no cross-protection against syngeneic, ganglioside GD 2 ϩ EL-4 thymoma cells was observed. Furthermore, this tumor-specific protection can be transmitted horizontally to naive, syngeneic SCID mice by passive transfer of CD8 ϩ T lymphocytes derived from immune animals. These results suggest that antibody-targeted delivery of cytokines provides a means to elicit effective immune responses against established tumors in the immunotherapy of neoplastic disease. ( J. Clin. Invest. 1996. 98: 2801-2804.)

Shift from Systemic to Site-Specific Memory by Tumor-Targeted IL-2

“…Indeed, we have previously observed that tumor-targeted IL-2 therapy resulted in the induction of a long-lived and transferable immunity if applied in the absence of any tumor-specific vaccination (28). This immunity was based on boosting pre-existing T cell responses (29).…”

Melanoma immunotherapy by targeted IL-2 depends on CD4+ T-cell help mediated by CD40/CD40L interaction

“…This can be accomplished by directing IL-2 into the tumor microenvironment with tumor-specific Ab-cytokine fusion proteins, called immunocytokines; this technique has been demonstrated in several xenograft and syngeneic preclinical animal models for colorectal carcinoma (29)(30)(31), prostate cancer (32), neuroblastoma (24,33), and melanoma (4)(5)(6)23). In two such model systems-murine colorectal carcinoma and melanoma-eradication of established metastases was mediated by CD8 + effector T cells.…”

Novel Therapeutic Approaches for Neuroblastoma

“…To date, immunocytokine research has focused on ADCC mediated by NK cells and on induction of CTL. An anti-GD2/IL-2 immunocytokine eradicated hepatic metastases of neuroblastomas in SCID mice that had been reconstituted with human lymphokine (IL-2) activated killer cells [153,154]. In contrast, the combination of monoclonal anti-GD2 antibody and IL-2 at doses equivalent to the immunocytokine only reduced tumor load.…”

“…In contrast, the combination of monoclonal anti-GD2 antibody and IL-2 at doses equivalent to the immunocytokine only reduced tumor load. In a syngeneic murine model of GD2 expressing melanoma, targeting with an anti-GD2 antibody/IL-2 immunocytokine resulted in generation of CD8+ T lymphocytes that could eradicate tumor as well as prevent tumor growth [154]. Based upon these data, phase I and II studies have tested a humanized anti-GD2/IL-2 immunocytokine (hu14.18/IL-2) in patients with refractory or relapsed neuroblastoma.…”