Immunotherapy of malignant disease with tumor antigen-specific monoclonal antibodies

Abstract

A few tumor antigen (TA)-specific monoclonal antibodies (mAb) have been approved by the Food and Drug Administration for the treatment of several major malignant diseases and are commercially available. Once in the clinic, mAbs have an average success rate of approximately 30% and are well tolerated. These results have changed the face of cancer therapy, bringing us closer to more specific and more effective biological therapy of cancer. The challenge facing tumor immunologists at present is represented by the identification of the mechanism(s) underlying the patients' differential clinical response to mAb-based immunotherapy. This information is expected to lead to the development of criteria to select patients to be treated with mAb-based immunotherapy. In the past, in vitro and in vivo evidence has shown that TA-specific mAbs can mediate their therapeutic effect by inducing tumor cell apoptosis, inhibiting the targeted antigen function, blocking tumor cell signaling, and/or mediating complement- or cell-dependent lysis of tumor cells. More recent evidence suggests that TA-specific mAb can induce TA-specific cytotoxic T-cell responses by enhancing TA uptake by dendritic cells and cross-priming of T cells. In this review, we briefly summarize the TA-specific mAbs that have received Food and Drug Administration approval. Next, we review the potential mechanisms underlying the therapeutic efficacy of TA-specific mAbs with emphasis on the induction of TA-specific cellular immune responses and their potential to contribute to the clinical efficacy of TA-specific mAb-based immunotherapy. Lastly, we discuss the potential negative effect of immune escape mechanisms on the clinical efficacy of TA-specific mAb-based immunotherapy.

Figure 1. Triggering of immune effector mechanisms by TA-specific mAb-based immunotherapy

TA-specific mAb may participate in host dependent immune effector mechanisms including (A) activation of (i) complement mediated phagocytosis and/or (ii) CDC; (B) induction of ADCC and/or (C) induction of tumor cell necrosis or apoptosis. The latter mechanisms result in the release of TA as well as the production of cytokines and opsonins that lead to (I) TA uptake, APC maturation and presentation of TA by APC; (II) generation of CD8(+) TA-specific CTL through CD4(+) T cell help, and (III) activation of CD4(+) T helper cells which leads to activation of NK cells, granulocytes and macrophage through release of Th1 cytokines, CD4(+) T cell-mediated killing, and activation of B cells and eosinophils through release of Th2 cytokines.

Figure 2. Induction of TA-specific CTL responses by TA-specific mAb-based immunotherapy

TA-specific mAb may enhance the generation and promote the survival of TA-specific CTL via several mechanisms. TA-specific mAb may (i) induce tumor cell death or activate (ii) ADCC and (iii) CDC. The latter results in 1) the formation of the lytic membrane-attack complex (MAC); 2) the generation of opsonins (C3b), and 3) the release of the anaphylatoxins C3a and C5a. The culmination of the above events (i, ii, iii) leads to the release of Th1 cytokines, (iv) the formation of TA-specific mAb-TA complexes and (v) the uptake of TA and TA-specific mAb-TA complexes by APC. Ultimately, mature DC present processed TA to CD4(+) and CD8(+) T cells, and promote the generation of (vi) TA-specific CTL.