Serendipity in a chase for a cure of cancer: origin and perspectives of immunochemotherapy from nitrogen mustard to chimeric antigen receptors

Abstract

In 2014, 50 years had passed since the first combination chemotherapy program — MOPP, was introduced for treat­ment of advanced neoplastic disease — Hodgkin lymphoma. This was 22 years after the first in-human use of nitrogen mustard as the first cytostatic agent given to the patient with advanced disseminated lymphoma. The principles used to develop the MOPP combination proved useful in designing treatment for patients with non-Hodgkin lymphomas and other tumours. Subsequent decades of clinical and laboratory research proved that the curative potential of chemotherapy was limited, and the greatest advances were possible in tumours with fast growth kinetics such as lymphoma and acute leukemia. It has taken 125 years of extensive search to find an antibody that would become a well-established, but for most of the time there has been an elusive concept of a selective antineoplastic agent. It was not until 1997 when the first monoclonal antibody specific to the common B-cell antigen CD20, including neo­plastic cells, was introduced and revolutionised the treatment of lymphoma. Since then, immunotherapy — not able to reach the level of clinical utility, has grown to fast developing and promising science of clinical research. Together with a number of monoclonal antibodies that act by mobilizing patients’ own cytotoxic mechanism or by blocking survival signals to cancer cells, there are now available antibodies that function as checkpoint inhibitors and unlock T-cell responses. This is as well as advanced technology for constructing specific chimeric antigen receptors that when transfected into autologous T-cells provide them with an attribute of a B-cell by means of immunoglobulin molecule able to target the cancer cell. In parallel, there has emerged a new science of small molecules interfering with pathogenic molecular pathways within a cell with a number of agents of already established use and value. Current knowledge and therapeutic opportunities make a perspective of precision and personalised oncology reality, where multicomponent treatment programs will be designed based on mechanism of action of chemotherapy, immunotherapy, and small molecules specifically assembled to the clinical context.