The main purpose of the present investigations was to provide proof of principle of feasibility, safety, and efficacy of a simple and inexpensive protocol for more effective cell-mediated immunotherapy of patients fully resistant to all available anti-cancer modalities. Based on successful cure with no severe side effects of the first patient treated with IMAK currently 28 years out (15), 32 additional incurable patients with different hematologic malignancies were recruited to assess the feasibility and safety of cell therapy with IMAK against multi-drug resistant disease. We have previously confirmed that DLI, especially DLI induced with IL-2 activated donor lymphocytes, can sometimes eliminate resistant malignant cells escaping following maximally tolerated myeloablative conditioning following allogeneic SCT [1–3]. There was a need to develop more effective treatment program for attempting elimination of malignant cells of hematopoietic origin resistant to all other available procedures, including allogeneic SCT and GvL induced by IL-2 activated DLI, since control of relapse was neither consistent even in patients with severe GVHD nor in patients with overt relapse. In contrast, our experience in our pre-clinical animal models [9, 12, 14] confirmed that immunotherapy based on transient circulation of mismatched activated lymphocytes against malignant target cells by readily available killer cells can be fast-acting and most effective, thus accomplished within a few days, before consistent rejection of anti-cancer effector cells occurs for prevention of GVHD. These observations supported by successful treatment of our first patient treated with IMAK with no clinically overt GVHD confirmed the expectation that elimination of malignant cells could be accomplished before rejection of mismatched killer cells, a mandatory pre-requisite for prevention of GVHD. As such, it seemed reasonable to anticipate that cure could be anticipated only when IMAK will be applied against MRD or against a relatively low tumor burden. Alternatively, the procedure would have to be repeated using different donor cells. Indeed, as shown in Table 3 and Fig. 1, most patients treated with IMAK using either haploidentical related donor cells or mismatched lymphocytes obtained from consenting unrelated donors showed evidence of response, and at least 6 of 22 patients observed for more than 5 years may even be considered cured.
Although our cumulative experience confirmed the feasibility, safety and efficacy of immunotherapy induced by IMAK, many questions remain to be answered. First, the role of IMAK needs to be confirmed in a prospective randomized clinical trial in different disease categories, both for treatment of patients with overt relapse and for treatment of patients at risk with minimal residual disease. Fortunately, induction of complete remission can be accomplished by conventional 1st line chemotherapy even in patients with high-risk hematologic malignancies at an early stage of the disease, or if indicated following high-dose chemotherapy and supportive autologous SCT, as per the routine procedure in patients with multiple myeloma. Therefore, once the safety and efficacy of IMAK can be confirmed, eradication of MRD resulting in cure could be easily accomplished at an early stage in patients with high risk disease before relapse occurs, when another opportunity of MRD may be difficult of impossible to accomplish.
Other important parameters that need to be investigated include whether treatment outcome could be improved by targeting the mismatched killer cells with relevant monoclonal antibodies. Also, as shown in Table 3, targeting T cell-depleted IMAK against 3 patients with AML was also successful, suggesting that IL-2 activated NK cells may be the dominant anti-cancer effector cells. Using T cell depletion or NK cells enriched killer cells will certainly minimize any risks of GVHD but it has to be determined if IMAK containing both IL-2 activated T and NK cells is more effective than IMAK based on the use of activated NK cells alone. Accordingly, we need to investigate if treatment with T cell-depleted or NK-enriched killer cells is worth the extra-complicated procedure and higher cost as compared with using an unmanipulated mixture of killer cells.
Another potentially important question is whether the anti-cancer effects inducible by IMAK could be improved by synergistic control of negative regulators such as regulatory T cells, checkpoint inhibitors, myeloid-derived suppressor cells and even mesenchymal stromal cells. Also, in the case of CD20-positive lymphoid malignancies, the anti-cancer effects induced by IMAK will have to be compared to the anti-cancer effects induced by CAR-T cells.
Taken together, the concept of fast and effective killing of malignant cells despite resistance to maximally tolerated doses of chemoradiotherapy and other available anti-cancer modalities by cell therapy alone, while avoiding much more complicated allogeneic SCT and the risks of GVHD, could possibly represent a new approach for more effective yet much simpler approach for immunotherapy of otherwise incurable hematologic malignancies. The available proof of principle should provide the basis and justification for future investigations and prospective clinical trials to investigate the safety and efficacy of cell-mediated immunotherapy based on the use of intentionally mismatched donor lymphocytes.
Remembering that no available anti-cancer modality can compete with the capacity of mismatched lymphocytes to reject any MHC mismatched target cells, including even kilograms of organ allografts in recipients sub-optimally immunosuppressed, our prediction based on multiple studies in pre-clinical animal models and our limited clinical experience is that IMAK application against a true stage of MRD could result in complete eradication of all resistant malignant cells. Future studies are indicated to prove or disprove our working hypothesis.