The future of cancer treatment: immunomodulation, CARs and combination immunotherapy

Abstract

In the past decade, advances in the use of monoclonal antibodies (mAbs) and adoptive cellular therapy to treat cancer by modulating the immune response have led to unprecedented responses in patients with advanced-stage tumours that would otherwise have been fatal. To date, three immune-checkpoint-blocking mAbs have been approved in the USA for the treatment of patients with several types of cancer, and more patients will benefit from immunomodulatory mAb therapy in the months and years ahead. Concurrently, the adoptive transfer of genetically modified lymphocytes to treat patients with haematological malignancies has yielded dramatic results, and we anticipate that this approach will rapidly become the standard of care for an increasing number of patients. In this Review, we highlight the latest advances in immunotherapy and discuss the role that it will have in the future of cancer treatment, including settings for which testing combination strategies and 'armoured' CAR T cells are recommended.

Figure 1. Immunomodulatory monoclonal antibodies and armoured chimeric antigen receptor (CAR) T cells overcome immune suppression

a | Overview of the immune inhibitory molecules that compromise endogenous T–cell antitumour activity. T cells are susceptible to immune inhibitory factors associated within the microenvironment that prevent their full antitumour activity. Such factors include cell surface proteins (such as programmed cell death 1 ligands 1 and 2 (PD-L1 and PD-L2)) and cytokines (such as TGF-β and IL-10). Regulatory T (T_REG) cells are representative of inhibitory cellular components of the tumour microenvironment (TME), which also include myeloid-derived suppressor cells, tumour-associated macrophages and other cell types non-depicted. b | Similarly to endogenous T cells, CAR T cells are susceptible to immune inhibitory factors present in the TME. c | Immunomodulatory monoclonal antibodies can be used to overcome local immunosuppression by either activating stimulatory receptors (such as TNFRSF9 (4-1BB) or OX40), or blocking suppressive receptors (for example, programmed cell-death 1 (PD-1) or cytotoxic T-lymphocyte antigen 4 (CTLA-4)). d | Armoured CAR T cells are engineered to express proteins that overcome immunosuppression associated with the TME (such as CD40L, IL-12 or TNFSF9 (4-1BBL)). Ag, antigen; APC, antigen-presenting cell; CD40L, CD40 ligand; Cy, cyclophosphamide; DC, dendritic cell; Flu, fludarabine; GITR, glucocorticoid-induced TNFR family related protein; GITRL, GITR ligand; HMGB1, high mobility group 1 protein; LAG-3, lymphocyte activation gene-3; PSer, phosphatidyl serine; scFv, single-chain variable fragment; TCR, T-cell receptor; TIGIT, T-cell immunoreceptor with immunoglobulin and ITIM domains; TIL, tumour -nfiltrating lymphocyte; TIM-3, T cell immunoglobulin and mucin domain 3.

Figure 2. Neoantigen presentation in the tumour microenvironment

a | Tumour cells can avoid elimination by immunoediting because of low neoantigen presentation (neoAg^low). This occurs as a result of a low level of somatic mutations, or because tumour cells might downregulate antigen processing or presentation. NeoAg^low tumours might escape detection by endogenous CTLs early in tumorigenesis, and therefore would expand without the pressure to co-evolve within an immunosuppressive microenvironment. This is the ideal setting for CAR T cells to direct a robust antitumour response. b | Tumours that present a high neoantigen burden (neoAg^high) can be eliminated during the immunoediting process (far right). Alternatively, neoAg^high tumour cells might co-evolve within an immunosuppressive tumour microenvironment (TME) that mediates avoidance of T-cell surveillance. This setting is the ideal situation for immune-modulating therapies with monoclonal antibodies to direct a robust antitumour response. c | Tumour types can be ranked by their relative presence of somatic mutations, and this classification can be used to indirectly estimate neoantigen burden. Tumours can be stratified on the basis of somatic mutation prevalence; tumour types with the most robust clinical responses to CAR T-cell therapy (red) or immune modulating mAbs (blue) are stratified by somatic mutation prevalence. ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; CAR, chimeric antigen receptor; CLL, chronic lymphocytic leukaemia; CTL, cytotoxic T cell; mAb, monoclonal antibody; MDSC, myeloid-derived suppressor cell; neoAg, neoantigen; PD-1, programmed cell death 1; PD-L1, programmed cell death 1 ligand 1; TAA, tumour-associated antigen; TAM, tumour-associated macrophage; TCR, T-cell receptor; TIL, tumour infiltrating lymphocyte; T_REG cell, regulatory T cell. Image reproduced from Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013),