Despite effective treatments achieving remission, cancer survivors often relapse, after which interventions become largely unsuccessful. One culprit is drug-resistant clones—pre-existing and evolving continuously—and another is tumor stem cells—repopulating, resilient, and poorly understood. With their unique features, once outgrowth has occurred, both culprits can evade standard therapies and prevail. The innate and adaptive immunity have been shown to play important roles in protecting the host through tumor immunosurveillance [1
]. Unfortunately, mechanisms of tumor-induced tolerance enable tumors to escape immunosurveillance [7
]. However, the delicate balance can be restored if we can design novel treatment that can break tolerance while promote innate and adaptive antitumor immunity.
Dendritic cells (DCs) capture, process, and cross-present antigens in the context of MHC class-I and costimulatory molecules to subsets of T-lymphocytes, and play critical roles in the regulation and development of distinct immune responses [8
] including (1) Th1 adaptive cell-mediated immunity (Th1 response) signified by interferon-γ (IFN-γ) secretion and play major roles in protection against pathogens and tumors [1
], (2) Th2, (3) Th17, and (4) T-regulatory responses (tolerance).
IFN-α is a type-1 IFN and a physiological danger signal [11
] can upregulate expression of MHC class-I molecules and costimulatory molecules on DCs, activate innate immunity, modulate DCs, promote Th1 response, help clonal expansion/survival and memory differentiation of T-lymphocytes [9
], and has been shown to be an effective vaccine adjuvant in animal models [14
] and clinical trials [15
]. The immunological consequences of tumor cell death induced by individual chemotherapy agents [17
] and the subsequent differentiation of DCs and T-lymphocytes in the ensuing 2-week span are of pivotal importance in influencing the development toward the distinct immune responses (Th1, Th2, Th17, or tolerance). Cytotoxic chemotherapy often results in prolonged severe leukopenia depriving DCs of proper maturation (differentiation), thus often resulting in a tolerant/dysfunctional immune state.
With recognition of the IFN-α qualities [9
], the pivotal role of DCs in the development of distinct immune responses [8
] and support from our preclinical data, we hypothesize that (1) combining IFN-α with effective non-marrow-suppressive antitumor agent(s) could induce innate immunity and Th1 response; (2) the antitumor immunity can help eradicating tumor cells including the drug-resistant clones and tumor stem cells upfront thus improve response rate; (3) most importantly, antitumor immunity can monitor continuously and eradicate the various continuing-evolving drug-resistant clones and the resilient tumor stem cells when they first emerge at the cellular/subclinical level prior to outgrowth, and this would delay/prevent relapse, ultimately leading to the improvements in progression-free survival (PFS) and overall survival (OS).
To test the hypothesis, we designed a new strategy aiming at developing innate immunity and Th1 response concomitant with partial response (PR) or complete response (CR) achieved by effective non-marrow-suppressive drug therapy. Gastrointestinal stromal tumor (GIST), a sarcoma with incidence of 5000/year in US, represents an excellent model to test our hypothesis for the following reasons. First, imatinib mesylate (IM, Gleevec®
], a selective inhibitor of ABL, KIT, PDGFRA/B, is highly effective, induces swift apoptosis/necrosis of GIST within 3–7 days [19
], and is non-marrow-suppressive, allowing proper DC and cytotoxic T-lymphocyte differentiation toward Th1 response. Second, GIST cell alterations include cancer/testis antigens [20
], tumor-antigens created by activating mutations in KIT
) or PDGFRA
] and new mutation(s) responsible for IM resistance [25
]. Third, IM-monotherapy trials in GIST patients have reported response rates (PR + CR) of 54% [28
], 52% [29
], and 48% [22
]. The median PFS remains ≤ 2 years [22
] mainly due to the development of IM resistance [25
]. Discontinuing IM resulted in high rate of relapse due to repopulating stem cells [31
]. Thus, better therapies for GIST are needed.
IM was reported to induce DC-mediated natural killer (NK) cell IFN-γ production [32
] and potentiate adaptive immunity through IM-off-target inhibition of KIT on DCs [34
] and inhibition of Ido [35
]; both IM-off-target immunological anti-GIST effects plus IM-inhibition of KIT/PDGFRA signaling contribute to the IM-monotherapy efficacy [22
] as described above and is less than satisfactory. We intend to bring out the full potential of anti-GIST immunity by a new strategy of combining peginterferon α-2b (PegIFNa2b, Peg-Intron®
] with IM and have demonstrated significant Th1 response, innate immunity, and highly promising clinical outcome comparing to IM-monotherapy [22
], strongly support all three parts of our hypothesis.