8-A842A Halperin7e_CH29_CROPPED2

C H A P T E R 2 9 Radioimmunotherapy and Unsealed Radionuclide Therapy

Tod W. Speer

INTRODUCTION The concept of a “magic bullet” or targeted therapy against a tumor was first proposed by Paul Ehrlich in 1898, ultimately allowing him to garner the Nobel Prize in 1908.As testimony to the complexities and challenges of his vision, it was not until a half a century later when radiolabeled antibodies were used in the clinic to target cancer. The modern exegesis for targeting agents does not limit the use of carrier molecules to mere anti- bodies. Successful targeting of tumor cells, with high affinity, can also be accomplished with antibody fragments, peptides, and affinity ligands. As the research and clinical arena ever so modestly disengage from intact antibodies as the carrier mol- ecule for the radionuclide, the impact of the immune system has been somewhat abrogated. Hence, the “immunotherapy contribution” of “radioimmunotherapy” (RIT) has become less pronounced. Perhaps, a more appropriate term for this tech- nology would be “targeted radionuclide therapy.” To date, RIT has made significant progress secondary to advances in cell biology, immunology, radiation oncology, nuclear physics, and chemical technology. There are greater than 8 million cancer deaths worldwide and nearly 600,000 cancer deaths in the United States annually. 1,2 Millions of can- cer patients each year exhaust available drug options and succumb to cancer. Current cancer drug development in the United States takes approximately 8 years and 1.3 billion dol- lars for FDA approval. 3 This process appears unsustainable. 4 RIT offers the potential to accelerate drug development. RIT exercises its cytotoxic action by delivering targeted molecular radiation to malignant tissue. Therefore, the success of RIT depends upon engineering a targeting construct that brings the radionuclide into close proximity of the target cell or tis- sue. The cytotoxic agent, the radionuclide, is always the same. Of course, there is a selected differential of energy deposition into tissue, depending upon the specific chosen radionuclide. Standard drug development relies upon identifying a differ- ent target receptor or pathway that is prevalent within a par- ticular type of cancer. Antibodies (or blocking agents) are then designed, over months or years, to interfere with the receptor or process. A cytotoxic evaluation is then performed. Not all antibodies are initially cytotoxic. Hence, the abovementioned timeline and cost prevail. Immunity refers to protection from disease or infectious agents. 5 Our immune system is composed of the cells and mol- ecules responsible for the immune response, which can be divided into an early (1- to 12-hour) reaction, termed innate immunity , and a late (1- to >7-day) reaction, termed adaptive immunity . The innate immune system comprises biochemi- cal and cellular mechanisms that exist prior to the introduc- tion of a “foreign” or infectious agent and results in a rapid response. The innate immune system consists of epithelial barriers, phagocytic cells (neutrophils, macrophages), natu- ral killer cells, the complement system, and cytokines. The adaptive immune system develops over time, becoming more effective with subsequent exposures of antigen. It exhibits the IMMUNOLOGY AND TARGETING CONSTRUCTS

ability to “remember” and to respond more quickly with con- tinued exposures to the same antigen. The adaptive immune system consists of lymphocytes and secreted antibodies. The adaptive immune system can be divided into humoral immu- nity and cell-mediated immunity. Concerning humoral immu- nity, B lymphocytes secrete antibodies for protection. With cell-mediated immunity, helper T lymphocytes either activate macrophages or cytotoxic T lymphocytes, which then directly destroy pathologic (infectious or malignant) cells. It is well known that the host’s immune system is impor- tant for preventing the growth and development of cancer. 6 A large body of literature exists supporting the concept that the host immune system interacts with tumorigenesis and tumor progression. It has been shown in animal models and in the clinic that cancer immune surveillance is exceedingly impor- tant. For example, mice with an impaired innate or adaptive immune system will be more susceptible to develop chemically induced or spontaneous cancers. Additionally, the malignant transformation of cells in animals and humans, caused by the accumulation of somatic mutations and/or the deregulation of oncogenes or tumor suppressor genes, results in the expression of tumor antigens (TAs). These TAs are often recognized by the immune system as documented byTA-specificT-cell precursors and natural killer cells, found in the peripheral blood of can- cer patients, capable of killing tumor cells. Further evidence of cancer immune surveillance exists in patients with genetic or drug-induced immunosuppression. Transplant patients exhibit a predisposition for certain malignancies (squamous cell car- cinoma, basal cell carcinoma, Kaposi sarcoma, melanoma, and lymphoma). Patients with Chédiak-Higashi and Wiskott- Aldrich syndrome demonstrate an increased rate of lympho- proliferative malignancies. Discontinuing immunosuppressive drugs in solid organ allograph patients with occult malignant melanoma has resulted in tumor regression. Despite the evidence of cancer genesis and progression in immune-compromised hosts, the majority of cancers develop in seemingly immune-competent individuals. The last decades of research have revealed that cancer cells have developed means to avoid immune detection and surveillance, either through the selection of nonimmunogenic tumor cells or the active suppression of the immune response. It has therefore been rightfully suggested that “tumor immune escape” be added to Hanahan and Weinberg’s six hallmarks of cancer (self-sufficiency in growth signals, insensitivity to antigrowth signals, tissue invasion and metastasis, limitless replicative potential, sustained angiogenesis, and evasion of apoptosis). Interestingly, recent progress has been achieved utilizing drugs for immune checkpoint blockade therapy by target- ing the programmed death protein (PD-1) with antibodies. Unfortunately, response rates have been limited. 7 Currently, the quest for the “Holy Grail” vaccine that turns the immune system against cancer remains elusive. 8 The targets for RIT typically consist of tumor-associated anti- gens (TAAs) expressed on the surface of tumor cells or in the abnormal extracellular matrix. The reason for this is because the cytotoxic radionuclide must be delivered preferentially to malignant tissue and should avoid normal tissue.To date, >2,000 TAAs have been identified (http://www.re3data.org/repository/ r3d100012052). One of the main methodologies used to identify TAAs is termed SEREX (serologic analysis of recombinant cDNA

Made with FlippingBook Online newsletter