The recent positive and exciting steps forward in the science and clinical applications of cancer immunotherapy are presented and discussed in this book. Progress in cancer immunotherapy has always depended critically on increasing knowledge of the underlying mechanisms of the immune response to cancer. Key areas of scientific understanding required to take cancer immunotherapy further forward, however, remain:
What antigenic determinants may most effectively stimulate an anticancer immune response?
What is the best biological context for antigen presentation to promote anticancer responses?
What non-specific stimulation, or removal of inhibition, of the immune response, may be used to enhance clinical efficacy?
How may we best combine vaccines and non-specific therapies?
Early attempts at non-specific enhancement of the immune response to cancer involved traditional adjuvants, often based on mycobacteria, or the systemic use of large doses of cytokines such as interleukin (IL)-2, IL-12 and IL-21. These are capable of enhancing immune responses to cancer in humans and do have some clinical efficacy but are poorly tolerated. More recently the use of immune checkpoint inhibitors (ICPIs) has non-specifically reduced inhibition of anticancer immune responses and has proved effective (covered elsewhere in this book). Even though they may also reduce inhibition of anti-self immune responses in some patients, they are more clinically tolerable when compared with the earlier strategies.
Tumour-associated antigens (TAAs) are found in both tumour and normal tissue but are overexpressed on tumour cells and/or expressed on dispensable tumour cells (e.g. cluster of differentiation [CD] 19 on B cell malignancies).1 Examples of TAAs include human telomerase reverse transcriptase and survivin. On the other hand, tumour-specific antigens (TSAs) are expressed only in tumour cells. TSAs are usually either neoantigens, resulting from the products of somatic gene mutations, such as the abnormal protein of mutated RAS, or abnormally expressed cancer testis antigens such as melanoma-associated antigen (MAGE). Functionally, TAAs are more likely to be tolerated by the immune system due to their normal self-expression, whereas TSAs are, by definition, immunologically non-self.
Our knowledge of the presentation of antigenic determinants on cancer cells that will stimulate an immune response has advanced steadily (Figure 9.1). TAAs have been explored as the basis of cancer vaccines or specific adoptive cellular therapy with some success. Most notably, recently, targeting antigen expression on lymphoid cells through the adoptive transfer of chimeric antigen receptor cells specific to CD19 in refractory acute lymphoid leukaemia or relapsed B cell lymphoma was successful.1 Some success has been reported using vaccines based on tumour lysates often mixed with antigen-presenting cells. In general, however, making use of TAAs that are present on normal tissues or tumour lysates has not yet resulted in effective vaccines for most solid tumours. Even when TAAs are overexpressed on cancer cells, their expression on normal tissues may still limit selective anticancer efforts. The combination of TAAs as vaccines together with ICPIs is being explored in ...