Towards Possible Cure of Cancer by Immunotherapy of Minimal Residual Disease Using Intentionally Mismatched Donor Lymphocytes

Cancer continues to be a leading cause of death worldwide. Considering lack of information about the causes of malignant transformation, except when viral agents seem to be involved, the universal dogma for treatment of cancer is based on ‘the more the better’ using available anti-cancer agents, attempting to eradicate the primary tumor by optimal resection, followed by chemotherapy or radiation therapy when indicated, considering additional treatment only as soon as secondary metastases become visible, usually focusing on aggressive chemotherapy as the standard of care. For patients with cancer not expected to respond adequately to conventional treatment, especially for treatment of hematological malignancies, myeloablative chemoradiotherapy followed by rescue with stem cell transplantation may be considered in an attempt to eradicate otherwise resistant malignant cells. Over the years it became apparent that in patients with primary resistant cancer or with metastatic disease, cure is unlikely to be accomplished. Indeed, relapse continues to be the single major obstacle in treatment of hematologic malignancies and many solid tumors as well, even following initial complete remission [1,2]. On the other hand, as the intensity of the regimen used for treatment of cancer or using high dose chemotherapy supported by stem cell transplantation (SCT) is escalated, the risks of procedure-related toxicity and mortality increase and recurrent disease may not be preventable [3]. In addition, increased incidence of late complications in patients treated with repeated courses of chemotherapy that may or may not increase survival are likely to impair the quality of life of longterm survivors and their supporting family. It became apparent that newer modalities must be introduced in order to improve the cure rate of patients with hematological malignancies and solid tumors as well as to improve the quality of life of successfully treated patients. For patients resistant to available chemotherapy, immunotherapy became in recent years an acceptable treatment as it was confirmed that activating patient’s immune system could be effective even against otherwise resistant disease. Unfortunately, in the absence of tumor-specific antigens and the unresponsiveness that develops between the immune system and the rapidly developing cancer cells, immunotherapy based on an attempt to immunize patients against cancer or using anti-cancer vaccines is far from being effective [4]. Clearly, the goal of effective immunotherapy should be based on an attempt to break the existing tolerance of the immune system against cancer cells, or Introduction Abstract