Emerging Immunotherapies for Non-Hodgkin Lymphomas: The Tortoise Approaches the Finish Line

• Lymphoma, non-Hodgkin
• Immunotherapy
• Immunotherapy, adoptive
• Antibodies, monoclonal
• Cancer vaccines

Disseminated malignancies continue to pose vexing problems for both patients and health care providers. Although localized malignant lesions can often be extirpated with surgery or radiation therapy, most metastatic neoplasms are difficult to cure despite systemic chemotherapy. Furthermore, the alopecia, nausea, myelosuppression, neurotoxicity, and nephrotoxicity that often accompany conventional chemotherapy are potent deterrents for many patients. Consequently, investigators and patients with cancer have long sought alternative therapies that might be effective while avoiding the dreaded side effects of chemotherapy. Immunologic interventions have been particularly appealing because they use “natural” components of the immune system to selectively eradicate malignant cells while leaving normal cells unharmed. Immunotherapeutic attempts have included “active” approaches, such as development of tumor vaccines, and “passive” or “adoptive” immunotherapy, in which components of the immune system (antibodies, interferons, interleukins, activated T lymphocytes) are produced exogenously before they are administered to patients with cancer. Of these strategies, monoclonal antibodies have achieved the most recent success and publicity.

Paul Ehrlich is widely credited as the visionary who initially promulgated the concept of therapeutic anticancer antibodies in the late 1800s and early 1900s. Little progress was made toward realization of his vision until 1975, when Kohler and Milstein published their seminal paper describing the mouse hybridoma method (1). This technique permitted large-scale production of high-quality, homogeneous antibodies of defined specificity. The imaginations of researchers, journalists, and the lay public were soon captured by the potential of monoclonal antibodies, and unrealistic predictions concerning the rapidity with which monoclonal antibodies would replace conventional cancer therapies were widely published in the lay and scientific literature. Unfortunately, early preclinical and clinical trials with monoclonal antibodies encountered a variety of obstacles: a paucity of well-defined tumor-specific antigens, interference from circulating free antigens shed from tumor cells into the bloodstream, the immunogenicity of murine antibodies, slow …