Immunotherapy of malignant melanoma using T cell-activating microbeads.

Abstract

Metastatic disease is the prime cause of death from many malignancies. Due to the multiple different lesions and the increased aggressiveness of the cancer cells, metastatic disease is often difficult to treat. Here, the introduction of immune checkpoint blockers (ICBs) has greatly helped to improve patients' prognosis by harnessing antitumor immunity, particularly anticancer T cells in multiple human cancers. Despite the success of ICBs in, for example, metastatic melanoma 2 major challenges remain in the field: therapy-limiting toxicities induced by systemic ICB administration and lack of a life-prolonging response in a substantial number of patients. Therefore, highly potent local immunotherapeutic approaches might offer a solution and enhance treatment of metastatic disease. Here, we describe antibody-functionalized paramagnetic microbeads as a means to fill this void. These microbeads are readily engulfed by the vast majority of human cancer cell line cells studied inducing direct cytotoxicity (first hit). Focusing on malignant melanoma, we further observed that loading the microbeads with a conventional anti-CD28 monoclonal antibody (bead-bound conventional anti-CD28 monoclonal antibody, BBC-28) not only efficiently induced proliferation and cytokine release by human T cells expressing CD28, but also enhanced killing of melanoma cells by melanoma-reactive T cells (second hit). Thus, we provide proof-of-concept data that BBC-28, after local application into, for example, skin metastases, may also induce a combination of direct toxicity and enhanced anticancer immunity, leading to efficient treatment of metastatic disease.