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Combination immunotherapy in cancer


Cancer immunotherapy – treatments that restore or enhance the immune system's ability to fight cancer – has achieved remarkable clinical results in multiple cancers over the past few years, generating a large amount of interest in this therapeutic modality.

An improved understanding of the immune response to cancer, as well as patient selection and biomarker development, has increased the number of patients who benefit from immunotherapies. However, although response rates and response durability have greatly improved with approved immunotherapeutic agents, a high percentage of patients fail to respond or progress. Combinatorial immunotherapy approaches are therefore likely to be the most viable strategy for improving responses and outcomes for patients. Such approaches may involve synergistic combinations of immunotherapy agents or combining immunotherapy agents with conventional cancer treatments such as radiotherapy or targeted therapy.

Using a selection of recent full-text articles and chapters from the Springer Nature portfolio, this themed collection explores the biological rationale in support of various combinatorial immunotherapy approaches. In addition, this collection provides an overview of progress in the synergistic design of immune-targeting combination therapies and highlights the challenges involved in tailoring such strategies to provide maximal benefit to patients. Over time this collection will be enhanced by the addition of specially commissioned articles and resources that provide further guidance to healthcare practitioners, as well as selected full-text articles sourced from other prominent publishers.

Overview of cancer immunotherapy

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

Therapies that treat cancer by modulating the immune response have led to unprecedented results in patients with advanced-stage tumors. This review discusses the latest advances in immunotherapy and its role in the future of cancer treatment.

Summary points
  • Cancer immunotherapies have the potential to generate robust antitumor responses; this can be achieved through several methods, such as modulatory antibodies or adoptive cellular therapy.
  • Since 2010, clinical trials using different immunotherapeutic approaches to treat patients with several tumor types have yielded unprecedented results.
  • In contrast with therapies that act on the tumor itself, immunotherapy-dependent antitumor responses can be sustained after the treatment has finished.
  • The optimal efficacy of immunotherapy will likely be achieved with designs that include combinations of different immunotherapeutic approaches, or immunotherapy combined with other cancer treatments.

Khalil​​​​​​​ DN et al. Nat Rev Clin Oncol 2016; 13: 273–290. doi:10.1038/nrclinonc.2016.25

Combining immune modulators

Evolving synergistic combinations of targeted immunotherapies to combat cancer

Immunotherapy is an effective treatment for many cancers. Progress in the synergistic design of immune-targeting combination therapies is discussed in this article, which also highlights the challenges in tailoring such strategies to maximize benefit to patients.

Summary points
  • Clinical trials have validated immuno-oncology as a new pillar of anticancer therapy.
  • Combinations could involve two (or more) sequential or simultaneous immunotherapies, and/or immunotherapies in combination with conventional cancer therapies.
  • The programmed cell death protein 1 (PD1)–PD ligand 1 axis seems to be the most promising immuno-oncology target, and its blockade is likely to become the main foundation for combination strategies in the foreseeable future.
  • The paradigm of immuno-oncology combinations is to block PD1 and cytotoxic T-lymphocyte-associated antigen 4 simultaneously; this blockade is synergistic and shows clinical benefit in patients with melanoma but has an increased frequency of immune-mediated, albeit clinically manageable, toxic effects.
  • Even if designing rational combinations that provide optimal benefit to patients with cancer is a challenging process, there are a number of different combination immuno-oncology therapies currently in development.

Melero​​​​​​​ I et al. Nat Rev Cancer 2015; 15: 457–472. doi: 10.1038/nrc3973

Enhancing the efficacy of checkpoint blockade through combination therapies

Antibodies that target coinhibitory receptors on T cells  are promising therapies for a range of malignancies. This chapter provides an overview of checkpoint blockade and combination therapy strategies.

Summary points
  • Antibodies targeting coinhibitory receptors on T cells (‘checkpoint blockade’), including cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed death-1 (PD-1), and others, have emerged as some of the most promising therapies for a broad range of malignancies.
  • Ipilimumab (anti-CTLA-4 antibody), pembrolizumab, and nivolumab (anti-PD-1 antibodies) are currently approved for patients with advanced melanoma.
  • Single agent checkpoint blockade is associated with 20–40% objective response rates in advanced melanoma and improved overall survival, whilst combination of anti-CTLA-4 and anti-PD-1 antibodies leads to an increased durable response rate compared to either antibody alone.
  • An important goal in the field is to combine checkpoint blockade with other immunotherapies (e.g., vaccines, T cell stimulatory agents, T cell transfer) and other types of therapy (e.g., radiation, targeted therapy, chemotherapy, surgery) to increase the fraction of patients that have responses, while maintaining the durability of response and minimizing the toxicity.
  • However, a lack of understanding about the precise mechanisms of action means it is currently difficult to predict whether these combinations will be synergistic or redundant.
  • Critical issues that need to be addressed in order to develop combination strategies include developing targeted delivery mechanisms to minimize adverse events associated with stimulating the immune system, and improving understanding of the mechanism of action of checkpoint blockade and the effects of non-immunotherapies on the immune response to tumors.

Juneja VR, LaFleur MW, Manguso RT, & Sharpe AH. In: Novel Immunotherapeutic Approaches to the Treatment of Cancer. Edited by Rennert PD. Springer International Publishing, 2016. doi:10.1007/978-3-319-29827-6_1

Combining checkpoint inhibitors with other modalities

Current clinical trials testing the combination of immunotherapy with radiotherapy

Evidence increasingly shows that radiation stimulates recruitment of immune mediators that enable anti-tumor responses. This article reviews the ongoing trials combining radiation with various immunotherapies and addresses the issues involved.

Summary points
  • Combining immunotherapy with radiation therapy (RT) is an actively growing field of clinical investigation for cancer treatment.
  • While several types of immunotherapy have been shown to work with RT to induce anti-tumor T cell responses, the requirements for a specific combination to be effective have not yet been fully explored.
  • Antibodies against two immune checkpoints, programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4), are currently being investigated in combination with RT in phase 1 and 2 studies and are showing promising results.
  • Inhibition of transforming growth factor-β (TGF-β), a cytokine with immunosuppressive activity, during and after RT allows priming of T cells to multiple tumor antigens and is currently being investigated in phase 1/2 trials, the results of which have yet to be obtained.
  • Preclinical data support the combination of RT and cytokines to generate an abscopal effect and phase 1–3 trials are currently ongoing with interleukin-2, granulocyte macrophage colony-stimulating factor, interferon-α, and tumor necrosis factor-α, amongst others.
  • Several questions remain unanswered and warrant consideration in any future trial design and evaluation including: the dose, size, and location of RT site; sequencing of therapy; selection of a meaningful endpoint; and, selection of appropriate patients.

Kang J, Demaria S, & Formenti S. J Immunotherapy Cancer 2016; 4: 51. doi:10.1186/s40425-016-0156-7

Improving cancer immunotherapy with DNA methyltransferase inhibitors

Solid tumors are often not responsive to immunotherapy but recent findings suggest that epigenetic modifying drugs can prime antitumor immunity. This review describes how DNA methyltransferase inhibitors may aid the establishment of antitumor immunity.

Summary points
  • Two DNA methyltransferases inhibitors (DNMTi) are currently approved by the US Food and Drug Administration: azacitidine and decitabine.
  • DNMTi have been shown to increase tumor immunogenicity by upregulating the production of the class I major histocompatibility complex (MHC I) whilst also increasing the levels of antigens displayed in MHC I, in particular cancer-testis antigens.
  • Furthermore, DNMTi have been demonstrated to stimulate natural killer cell- and CD8 T cell-mediated cytotoxicity by inducing the expression of chemokines and activating associated ligands on the surface of tumors cells.
  • DNMTi can also decrease natural and tumor-induced immunosuppression by regulatory adaptive and innate immune cells.
  • The ability of DNMTi to widely prime the immune system makes them a great candidate for combinations with other immunotherapies, particularly immune checkpoint blockade.
  • Multiple phase 1 clinical trials employing DNMTi in combination with a variety of immune-based therapies are currently ongoing.

Saleh MH, Wang L, & Goldberg MS. Cancer Immunol Immunother 2016; 65: 787–796. doi:10.1007/s00262-015-1776-3

Influences of BRAF inhibitors on the immune microenvironment and the rationale for combined molecular and immune targeted therapy

This review discusses the role of the BRAF/mitogen activated protein kinase pathway in modulating antitumor immunity and how this provides a rationale for combining BRAF- targeted therapy with immunotherapy to enhance therapeutic responses.

Summary points
  • Studies have clearly demonstrated that inhibition of the BRAF/mitogen activated protein kinase (MAPK) pathway has a profound effect on antitumor immunity and the tumor microenvironment as a whole through a number of different mechanisms, including effects on dendritic cell function and natural killer cell activation.
  • In addition to the favorable immune effects of BRAF/MAPK pathway blockade, immune mechanisms of therapeutic resistance to these agents also exist—including through the induced expression of immunomodulatory molecules within the tumor microenvironment, and through stromal-mediated immunosuppression.
  • This provides a sound rationale for developing combination strategies with targeted therapy and immunotherapy, though problems exist regarding optimal combination regimens and associated toxicity, and the optimal timing and sequence of therapy.
  • Ongoing trials highlight these difficulties; insights have been gained through longitudinal tissue- and blood-based analyses in patients during treatment with these agents as monotherapy, indicating that translational studies should be built into trials to better inform mechanisms of response and resistance to these regimens and to gain insight into potential mechanisms of toxicity.
  • Treatment regimens need to be carefully studied in preclinical models if we are to understand the mechanisms behind potential treatment combinations.
  • A personalized approach is required if optimal combination strategies are to be designed that improve therapeutic responses whilst reducing resistance to therapy.

Reddy SM, Reuben A, & Wargo JA. Curr Oncol Rep 2016; 18: 42. doi:10.1007/s11912-016-0531-z

Targeted therapy and checkpoint immunotherapy combinations for the treatment of cancer

Advances in cancer treatment have been driven by the development of targeted therapies and therapies that stimulate antitumor immunity. This review discusses the immune-modulating effects of targeted therapies and how they may synergize with immunotherapy.

Summary points
  • Targeted therapies inhibit tumor-intrinsic drivers of growth and can elicit significant but transient clinical responses.
  • Checkpoint inhibitors are immunotherapies that relieve suppressive signals acting on host T cells to unleash antitumor T cell activity. They can elicit durable responses in subsets of patients across multiple tumor types.
  • In addition to the inhibition of oncogenic signaling pathways and tumor-associated angiogenesis, targeted therapies can enhance aspects of cancer immunity, such as tumor antigenicity, T cell trafficking, or T cell infiltration into tumors.
  • This provides a rationale for combining them with checkpoint inhibitors or other cancer immunotherapies that may lead to synergistic efficacy.
  • Considerations for the clinical development of combinations of targeted therapies and immunotherapies include optimizing dosing regimens, minimizing treatment related toxicities, and selecting appropriate biomarkers and endpoints to assess efficacy.

Hughes PE, Caenepeel S, & Wu LC. Trends Immunol 2016; 37: 462–4-76. doi: 10.1016/

Immune effects of chemotherapy, radiation, and targeted therapy and opportunities for combination with immunotherapy

It is not completely clear how best to incorporate molecularly targeted and immune-targeted therapies into combination regimens in cancer treatment. This review discusses these combination approaches and their potential for cancer management.

Summary points
  • Though monotherapy regimens for cancer have yielded some success, there are significant limitations with regard to response rates and duration of therapy.
  • Given the growing success of immunotherapy regimens across cancer types, there is significant interest in combining immunotherapeutic approaches with standard and novel agents (ie, chemotherapy, radiotherapy, targeted therapy) to exploit potential synergy.
  • The premise behind this is that several treatments may make a tumor more immunogenic, thus enhancing the effects of immunotherapy when these strategies are given in combination.
  • Rational design of these combination strategies requires a deep understanding of the effects of each therapy alone (and in combination) on host anti-tumor immunity.
  • The influence of chemotherapy, radiation therapy, and molecularly targeted therapy on the host anti-tumor immune response and the host anti-host response (ie, autoimmune toxicity) must be taken into consideration when designing immunotherapy-based combination regimens.

Wargo JA, Reuben A, Cooper ZA, Oh KS, & Sullivan RJ. Semin Oncol 2015;42: 601–616. doi: 10.1053/j.seminoncol.2015.05.007

Combination immunotherapy approaches in specific tumors

Definitive chemoradiation alters the immunologic landscape and immune checkpoints in head and neck cancer

Studies have suggested potential synergy between high dose per fraction focal radiation and immunotherapy. The results here demonstrate that fractionated chemoradiation leads to quantifiable effects in circulating immune mediators.

Summary points
  • Circulating immunologic factors were prospectively evaluated in a group of patients with head and neck squamous cell carcinoma (HNSCC) undergoing definitive radiation therapy with or without concurrent chemotherapy to characterize the systemic effects of treatment.
  • Treatment not only increased circulating CD8+ T-effector cells, but also myeloid-derived suppressor cells, regulatory T cells, and checkpoint receptor-expressing T cells, particularly programmed death 1-positive T cells.
  • Significant decreases in the chemokine CXCL10 and increases in CXLC16 were also noted.
  • Increased CXCL10 levels have been associated with worse cancer-specific outcomes whereas increases in CXCL16 have been shown to attract tumor-infiltrating T cells or natural killer cell cells.
  • T-cell receptor (TCR) sequencing and seromic analyses also suggested that radiation promotes antitumor immunity and that chemoradiation can potentially enrich the proportion of top TCR clones in select patients.
  • However, evidence for inhibitory effects that may limit the immune-stimulating effects of chemoradiation was observed.
  • The findings suggest that radiation-induced effects on the local tumor microenvironment in patients with HNSCC may translate into quantifiable immune effects in circulating immune mediators, TCR repertoires, and potential anti-tumor antibody responses.

Sridharan​​​​​​​ V et al. Br J Cancer 2016; 115: 252–260. doi:10.1038/bjc.2016.166

Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma

Results from this small study suggest that the combination of the antiangiogenic agent bevacizumab and the checkpoint inhibitor atezolizumab improves antigen-specific T-cell migration in metastatic renal cell carcinoma more than either single agent alone.

Summary points
  • Anti-tumor immune activation by checkpoint inhibitors has shown strong responses in a variety of cancers, but a combination of approaches is required to extend this benefit.
  • Preclinical models have shown that tumor-derived vascular endothelial growth factor (VEGF) limits immune cell activity while anti-VEGF therapy augments intra-tumoral T-cell infiltration. This study investigated how VEGF blockade with bevacizumab could improve checkpoint inhibition with atezolizumab in metastatic renal cell carcinoma (mRCC).
  • Levels of intra-tumoral CD8+ T cells increased following combination treatment with bevacizumab and atezolizumab.
  • Furthermore, a related increase was observed in intra-tumoral class I major histocompatibility complex (MHC-I), T-helper 1 and T-effector markers, and chemokines, most notably fractalkine (CX3CL1).
  • Fractalkine receptor was also observed to increase on peripheral CD8+ T cells with treatment.
  • Finally, increases in trafficking lymphocyte were observed in tumors following bevacizumab and combination treatment.
  • The authors conclude that the combination of atezolizumab and bevacizumab improves antigen-specific T-cell migration in mRCC.

Wallin​​​​​​​ JJ et al. Nat Commun 2016; 7: 12624.doi: 10.1038/ncomms12624

Combinatorial immunotherapy for melanoma

This review explores the evolution of melanoma treatments with particular attention to the history and recent advances in melanoma immunotherapy, novel combinations of these modalities, and their potential to offer novel therapeutic options for patients.

Summary points
  • More than any other solid tumor, immunotherapy has shown the greatest promise in the treatment of advanced melanoma.
  • Although response rates and response durability have greatly improved with recently approved immunotherapeutic agents, a high percentage of patients fail to respond or progress.
  • Combinatorial approaches are therefore likely to be the most viable strategy for improving outcomes in patients with advanced-stage melanoma.
  • Approaches that combine immunotherapies either with each other or with other modalities (e.g., targeted therapy, radiation therapy, surgery) are under active investigation.
  • The combination of cytotoxic T-lymphocyte-associated antigen-4 and programmed cell death protein-1 immune checkpoint inhibition has been shown to provide the most promising response data to date and is FDA-approved for the treatment of advanced melanoma.

George DD, Armenio VA, &Katz SC. Cancer Gene Ther 2017; 24: 141–147. doi:10.1038/cgt.2016.56

Combined immune checkpoint protein blockade and low dose whole body irradiation as immunotherapy for myeloma

Results from this preclinical study indicate that blocking programmed death-1 (PD-1)/PD-1 ligand interactions in conjunction with other immune checkpoint proteins provides synergistic anti-tumor efficacy following lymphodepletive doses of whole body irradiation.

Summary points
  • Multiple myeloma is generally considered to be an incurable disease and successful treatments will likely require multi-faceted approaches incorporating conventional drug therapies, immunotherapy and other novel treatments.
  • Previously, a combination of transient lymphodepletion (sublethal whole body irradiation) and programmed death-1 (PD-1)/PD-1 ligand blockade generated anti-myeloma T cell reactivity capable of eliminating established disease and so it was hypothesized that blocking a combination of checkpoint receptors would boost anti-tumor immunity.
  • Elevated percentages of PD-1, 2B4, lymphocyte activation gene-3 (LAG-3), and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) proteins were expressed on T cells of bone marrow from myeloma-bearing mice that had been treated with a low dose of whole body irradiation and combinations of blocking antibodies.
  • When PD-L1 blockade was combined with blockage of antibodies to LAG-3, TIM-3 or cytotoxic T-lymphocyte antigen 4, synergistic or additive increases in survival were observed (from approximately 30% to >80%); this also correlated with increased frequencies of tumor-reactive CD8 and CD4 T cells.
  • These data indicate that blocking PD-1/PD-L1 interactions in conjunction with other immune checkpoint proteins provides synergistic anti-tumor efficacy following lymphodepletive doses of whole body irradiation and may be a promising combination strategy for myeloma and other hematologic malignancies.

Jing W et al. J Immunotherapy Cancer 2015; 3: 2. doi:10.1186/s40425-014-0043-z