Protective Antitumor Immunity Induced by a Costimulatory Thalidomide Analog in Conjunction with Whole Tumor Cell Vaccination Is Mediated by Increased Th1-Type Immunity

Abstract

Thalidomide and its novel T cell costimulatory analogs (immunomodulatory drugs) are currently being assessed in the treatment of patients with advanced cancer. However, neither tumor-specific T cell costimulation nor effective antitumor activity has been demonstrated in vivo. In this study, we assessed the ability of an immunomodulatory drug (CC-4047/ACTIMID) to prime a tumor-specific immune response following tumor cell vaccination. We found that the presence of CC-4047 during the priming phase strongly enhanced antitumor immunity in the vaccinated group, and this correlated with protection from subsequent live tumor challenge. Protection was associated with tumor-specific production of IFN-γ and was still observed following a second challenge with live tumor cells 60 days later. Furthermore, CD8+ and CD4+ splenocyte fractions from treated groups secreted increased IFN-γ and IL-2 in response to tumor cells in vitro. Coculture of naive splenocytes with anti-CD3 mAb in the presence of CC-4047 directly costimulated T cells and increased Th1-type cytokines. Our results are the first to demonstrate that a costimulatory thalidomide analog can prime protective, long-lasting, tumor-specific, Th1-type responses in vivo and further support their ongoing clinical development as novel anti-cancer agents.

Phase I study to determine the safety, tolerability and immunostimulatory activity of thalidomide analogue CC-5013 in patients with metastatic malignant melanoma and other advanced cancers

“…Support for this concept has been obtained in a vaccination model of colorectal cancer in which another IMiD was shown to generate a protective and long-lasting antitumour response in vivo (Dredge et al, 2002b).…”

“…The ability to costimulate T cells has been associated with an increased Th1-type cytokine response and suggests that in certain clinical settings, IMiD analogues are likely to act as adjuvants to promote T-cell responses, thereby contributing to antitumour activity in vivo. In this regard, IMiDs have been shown to augment antitumour responses in vivo, leading to long-term protection from tumour challenge (Dredge et al, 2002b). Antiangiogenic activity has provided the rationale for the use of this class of compound as anticancer agents and, although unproven, this has often been linked to thalidomide's teratogenicity.…”

Chronic GVHD: Where are we? Where do we want to be? Will immunomodulatory drugs help?

“…78 Several features of pomalidomide suggest it may be useful in treating cGVHD including: (1) in-vitro suppression of TNFa (human monocytes); 79 (2) increasing Th 1 (mouse cancer vaccine, human CD4 þ T cells in vitro); 80,81 (3) suppression of Th 2 (mouse cancer vaccine); 80 and (4) stimulation of IL-12 and sIL-2Ra (humans). 78,80 However, other effects of pomalidomide have potential adverse effects in treating cGVHD including: (1) increased CD45RO þ (memory) CD4 and CD8 T cells (humans); 78 (2) decreased T regs ; 82 (3) increased Th 2 (polarized human CD4 þ T cells in vitro); 81 and (4) increased B cells (in-vitro human CD19 þ cells). 83 Recently, cereblon was identified as an essential mediator of Ienalidomide and pomalidomide anticancer activity in multiple myeloma.…”

Recent clinical studies of the immunomodulatory drug (IMiD®) lenalidomide

“…IMiDs also activate the innate component of the immune system: enhanced natural killer cell cytotoxicity leading directly to multiple myeloma cell lysis . The ability of IMiDs to activate innate immune responses may be crucial to the generation of effective adaptive antitumour responses in vivo, although this area remains relatively unexplored, as has a potential role for IMiDs in the enhancement of protective antitumour immunity (Dredge et al, 2002b).…”