Abstract
Host immunity recognizes and eliminates most early tumor cells, yet immunological checkpoints, exemplified by CTLA-4, PD-1, and PD-L1, pose a significant obstacle to effective antitumor immune responses. T-lymphocyte co-inhibitory pathways influence intensity, inflammation and duration of antitumor immunity. However, tumors and their immunosuppressive microenvironments exploit them to evade immune destruction. Recent PD-1 checkpoint inhibitors yielded unprecedented efficacies and durable responses across advanced-stage melanoma, showcasing potential to replace conventional radiotherapy regimens. Neverthless, many clinical problems remain in terms of efficacy, patient-to-patient variability, and undesirable outcomes and side effects. In this review, we evaluate recent advances in the immuno-oncology field and discuss ways forward. First, we give an overview of current immunotherapy modalities, involving mainy single agents, including inhibitor monoclonal antibodies (mAbs) targeting T-cell checkpoints of PD-1 and CTLA-4. However, neoantigen recognition alone cannot eliminate tumors effectively in vivo given their inherent complex micro-environment, heterogeneous nature and stemness. Then, based mainly upon CTLA-4 and PD-1 checkpoint inhibitors as a “backbone,” we cover a range of emerging (“second-generation”) therapies incorporating other immunotherapies or non-immune based strategies in synergistic combination. These include targeted therapies such as tyrosine kinase inhibitors, co-stimulatory mAbs, bifunctional agents, epigenetic modulators (such as inhibitors of histone deacetylases or DNA methyltransferase), vaccines, adoptive-T-cell therapy, nanoparticles, oncolytic viruses, and even synthetic “gene circuits.” A number of novel immunotherapy co-targets in pre-clinical development are also introduced. The latter include metabolic components, exosomes and ion channels. We discuss in some detail of the personalization of immunotherapy essential for ultimate maximization of clinical outcomes. Finally, we outline possible future technical and conceptual developments including realistic in vitro and in vivo models and inputs from physics, engineering, and artificial intelligence. We conclude that the breadth and quality of immunotherapeutic approaches and the types of cancers that can be treated will increase significantly in the foreseeable future.
Highlights
Non-surgical treatments of cancer have not generated completely satisfactory results to date
Combinations simultaneously targeting different components of tumor development/progression can significantly enhance efficacy, response rates, and durability relative to single-agent firstand second-generation immunotherapies [40, 41] (Figure 6). These “third-generation” novel combinations are increasingly based upon the programmed cell death protein 1 (PD-1)/programmed cell death protein 1 ligand (PD-L1) blockade “backbone,” given its relatively favorable safety profile and efficacy compared to other checkpoint inhibitors (Table 2) [12, 14, 25, 40, 41]
Mice with melanoma rich in macrophages had dramatically enhanced response to immune checkpoint inhibitors and survival when co-treated with IPI-549: Monotherapy with anti-cytotoxic Tlymphocyte-associated protein 4 (CTLA-4) or antiPD-1 produced total remission in 20% of cases whilst addition of IPI-549 increased this to 80%
Summary
Non-surgical treatments of cancer (mainly conventional chemotherapy, targeted biological therapies, and radiotherapy) have not generated completely satisfactory results to date. Combinations simultaneously targeting different components of tumor development/progression can significantly enhance efficacy, response rates, and durability relative to single-agent firstand second-generation immunotherapies [40, 41] (Figure 6) These “third-generation” novel combinations are increasingly based upon the PD-1/PD-L1 blockade “backbone,” given its relatively favorable safety profile and efficacy compared to other checkpoint inhibitors (Table 2) [12, 14, 25, 40, 41]. Improved immune targeting and combination therapies owe their enhanced efficacy over monotherapies to the strengthening of multiple components of T-cell anti-tumor responses This improvement results from (i) functioning of effector T-cells inside TME, including the capacity to evade immunosuppressive checkpoints and soluble factors; (ii) effective extravasation of T-lymphocytes from lymphoid organs into TME; and (iii) production of adequate quantities of effector T-cells inside lymphoid organs [22]. Simultaneous modulation of costimulatory and coinhibitory T-cell receptors warrants further investigation with careful consideration to the timing of the combination treatment [92]
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