Re: cancer immunotherapy: from the past, to the present, to the future 리뷰

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beyond reason

Curr Oncol. 2020 Apr; 27(Suppl 2): S87–S97.

Published online 2020 Apr 1. doi: 10.3747/co.27.5223

PMCID: PMC7194005

PMID: 32368178

A review of cancer immunotherapy: from the past, to the present, to the future

K. Esfahani, MD MSc,* L. Roudaia, MD,* N. Buhlaiga, MD,* S.V. Del Rincon, PhD,† N. Papneja, MD,* and W.H. Miller, Jr, MD PhD

Author information Copyright and License information Disclaimer

This article has been cited by other articles in PMC.

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Abstract

Compared with previous standards of care (including chemotherapy, radiotherapy, and surgery), cancer immunotherapy has brought significant improvements for patients in terms of survival and quality of life. Immunotherapy has now firmly established itself as a novel pillar of cancer care, from the metastatic stage to the adjuvant and neoadjuvant settings in numerous cancer types.

In this review article, we highlight how the history of cancer immunotherapy paved the way for discoveries that are now part of the standard of care. We also highlight the current pitfalls and limitations of cancer checkpoint immunotherapy and how novel research in the fields of personalized cancer vaccines, autoimmunity, the microbiome, the tumour microenvironment, and metabolomics is aiming to solve those challenges.

Keywords: Immune checkpoint inhibitors, personalized cancer vaccines, immune-related adverse events, microbiome studies, metabolomics

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INTRODUCTION

The field of immuno-oncology has been transformational in the care of cancer patients. William B. Coley, now widely accepted as the father of immunotherapy, first attempted to harness the power of the immune system for treating cancer in the late 19th century. As an orthopedic surgeon who operated on patients with bone sarcomas, he noticed that some patients with significant postoperative wound infections—a common occurrence when aseptic technique had not yet been optimized—would undergo spontaneous regression of their unresected tumours. Beginning in 1891, Coley injected more than a thousand patients with mixtures of live and inactivated bacteria such as Streptococcus pyogenes and Serratia marcescens with the hope of inducing sepsis and strong immune and antitumour responses. His cocktail of bacteria became widely known as “Coley’s toxin” and represents the first documented active cancer immunotherapy intervention1. Coley achieved durable complete remissions in several types of malignancies, including sarcoma, lymphoma, and testicular carcinoma. However, the lack of a known mechanism of action for Coley’s toxin and the risks of deliberately infecting cancer patients with pathogenic bacteria caused oncologists to adopt surgery and radiotherapy as alternative standard treatments early in the 20th century2.

It would take more than half a century before a better understanding of the key mediators of sepsis would shed some light on the mechanisms of action of Coley’s toxin. Those mediators constitute a cytokine family including interleukins, interferons, and chemokines3. Once again, the race was on to apply those novel discoveries to cancer therapy4. Physicians and researchers achieved modest success with this novel approach, occasionally inducing clinical remissions with high-dose interleukin 2 (il-2) in metastatic renal cell carcinoma5 and debatable responses with interferon in stages iii and iv melanoma6. Those modest successes were often counterbalanced with significant adverse events. Although novel methods of delivery such as pegylation would abate some of the toxicities, the sporadic and unpredictable immune responses seen with those therapies meant that only a small, carefully selected subgroup of cancer patients would benefit.

The next revolutionary wave in cancer immunotherapy came with the better understanding of the process of immune surveillance, by which innate immune cells eliminate cancer cells. The recent discovery of T cell immune checkpoints, such as ctla-4 and PD-1, propelled the field of immuno-oncology into its current era and saw the awarding of the 2018 Nobel prize in Physiology or Medicine to Drs. Allison and Honjo. Those hardwired signals have the crucial task of maintaining a fine balance between immune surveillance against foreign pathogens or abnormal cells and autoimmunity. Blocking those T cell surface receptors results in enhanced autoimmunity that induces an immune response against tumours, but can also increase the chance of autoimmune reactions.

In this review article, we highlight the current standards of care in cancer immunotherapy, with a strong focus on immune checkpoint inhibitors (icis), their limitations and pitfalls, and promising novel approaches.

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REVIEW

Overview of Checkpoint Inhibitors

Cancer immuno-editing is the process by which various immune system components protect the host against primary tumour development or enhance tumour escape, or both, either by sculpting tumour immunogenicity or attenuating antitumour immune responses7. The process is tightly regulated by immune checkpoints, which are immune-cell surface receptors controlling either the activation or the inhibition of immune responses. Activation of the immune system is, on the one hand, the desired outcome to achieve tumour control, but on the other hand, responsible for autoimmunity. The discovery and development of monoclonal antibodies against the inhibitory immune checkpoints ctla-4 and PD-1 have resulted in dramatic antitumour responses by the up-regulation of immune activation at various stages of the immune cycle.

Immune checkpoint inhibitor therapies are now widely indicated in numerous cancer types (Table I). Furthermore, numerous ongoing clinical trials are assessing the potential of other agonistic or inhibitory checkpoints to affect tumour-related outcomes (Table II). The checkpoints are not equal in their potential. For example, the agonistic OX40 antibody has modest clinical activity, but the CD28 antibody—even at very subtherapeutic doses—resulted in massive cytokine syndrome and the intensive-care hospitalization of the first 6 healthy volunteers treated8. In that light, finding the right combination of ici therapy to induce the optimal amount of immune activation remains an active area of clinical research.

TABLE I

Indications for immune checkpoint inhibitors in advanced-stage cancers, as currently approved by Health Canadaa

AgentMelanomaNSCLCRCCSCHNNBladderMerkel cell carcinomaHepatocellular carcinomaHodgkin lymphoma

CTLA-4 inhibitor
Ipilimumab	All lines of Tx
PD-1 inhibitors
Pembrolizumab	All lines of Tx	All lines of Tx	2nd line Tx	After ASCT
Nivolumab	All lines of Tx	2nd line Tx	2nd line Tx	2nd line Tx	2nd line Tx	After ASCT
PD-L1 inhibitors
Atezolizumab	2nd line Tx	2nd line Tx
Avelumab	2nd line Tx
Durvalumab	After CTxRT in stage III disease	2nd line Tx
Combination CTLA-4 and PD-1 inhibition
Ipilimumab–nivolumab	1st line Tx	1st line Tx

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aObtained 25 May 2019 from Health Canada’s Drug Product Database (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database.html).

NSCLC = non-small-cell lung cancer; RCC = renal cell carcinoma (clear cell); SCCHN = squamous-cell carcinoma of head and neck; Tx = treatment; ASCT = autologous stem-cell transplantation; CTxRT = chemoradiotherapy.

TABLE II

Agonistic and antagonistic immune checkpoint modulators currently under investigation

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TargetDrugCompanyClinical phase

Costimulatory or agonist antibodies
4-1BB (CD137)	Utomilumab	Pfizer Canada, Kirkland, QC	I
Urelumab	Bristol–Myers Squibb, New York, NY, U.S.A.	I/II
INBRX-105	Inhibrx, San Diego, CA, U.S.A.	I
ICOS (CD278)	GSK3359609	GlaxoSmithKline, Mississauga, ON	I/II
JTX-2011	Jounce Therapeutics, Cambridge, MA, U.S.A.	I/II
GITR (CD357)	TRX 518-001	Leap Therapeutics, Cambridge, MA, U.S.A.	I/II
MK-4166	Merck, Kenilworth, NJ, U.S.A.	I
BMS-986156	Bristol–Myers Squibb, New York, NY, U.S.A.	I/II
INCAGN01876	Incyte Biosciences International, Wilmington, DE, U.S.A.	I/II
CD70	ARGX-110 (cusatuzumab)	Argenx, Breda, Netherlands	I/II
CD27	CDX-1127 (varlilumab)	Celldex Therapeutics, Hampton, NJ, U.S.A.	I/II
OX40 (CD134)	PF-0451860	Pfizer Canada, Kirkland, QC	I/II
MEDI0562/6469/6383	AstraZeneca Canada, Mississauga, ON	I
GSK3174998	GlaxoSmithKline, Mississauga, ON	I
BMS-986178	Bristol–Myers Squibb, New York, NY, U.S.A.	I/II
CD40	CP870893	Pfizer Canada, Kirkland, QC	I
APX005M	Bristol–Myers Squibb, New York, NY, U.S.A.	I/II
Co-inhibitory or antagonist antibodies
VISTA (B7-H5)	CA-170	Curis, Lexington, MA, U.S.A.	I
CCR4 (CD194)	Mogamulizumab	Kyowa Kirin, Tokyo, Japan	I/II
B7-H3 (CD276)	MGD009	Novartis Pharmaceutical, Ottawa, ON	I
8H9	Y-mAbs Therapeutics, New York, NY, U.S.A.	I
TIM-3	TSR-022	Tesaro, Waltham, MA, U.S.A.	I
MBG453	Novartis Pharmaceutical, Ottawa, ON	I/II
Sym023	Symphogen A/S, Ballerup, Denmark	I
MEDI9447 (oleclumab)	AstraZeneca Canada, Mississauga, ON	I
LAG-3 (CD223)	BMS-986016 (relatlimab)	Bristol–Myers Squibb, New York, NY, U.S.A.	I/II
IMP321 (eftilagimod alpha)	Prima BioMed, Sydney, Australia	II
LAG525	Novartis Pharmaceutical, Ottawa, ON	I/II
KIR (2DL1–3)	Lirilumab	Bristol–Myers Squibb, New York, NY, U.S.A.	I/II
IDO-1,2	Indoximod	NewLink Genetics, Ames, IA, U.S.A.	II
Epacadostat	Incyte Biosciences International, Wilmington, DE, U.S.A.	II
TIGIT	Tislelizumab	BeiGene, Beijing, P.R.C.	I/II/III
BMS-986207	Bristol–Myers Squibb, New York, NY, U.S.A.	I/II
MTIG7192A	Genentech, San Francisco, CA, U.S.A.	II/III
AB154	Arcus Biosciences, Hayward, CA, U.S.A.	I/II
A2aR	Ciforadenant	Corvus Pharmaceuticals, Burlingame, CA, U.S.A.	I
Transforming growth factor β	M7824	EMD Serono, Rockland, MA, U.S.A.	I/II
Galunisertib	Eli Lilly and Company, Indianapolis, IN, U.S.A.	II
CD47	TTI-621	Trillium Therapeutics, Mississauga, ON	I
CD73	MEDI9447 (oleclumab)	AstraZeneca Canada, Mississauga, ON	I
Other pathways
Toll-like receptors	Poly-ICIC	Ludwig Institute for Cancer Research, New York, NY, U.S.A.	I
MGN1703 (lefitolimod)	Mologen, Berlin, Germany	I
SD-101	Dynavax Technologies Corporation, Emeryville, CA, U.S.A.	I/II
DSP-0509	Boston Biomedical, Cambridge, MA, U.S.A.	I/II
Rintatolimod	Hemispherx Biopharma, Philadelphia, PA, U.S.A.	II
CMP-001	Checkmate Pharmaceuticals, Cambridge, MA, U.S.A.	II
Interleukin 2 receptor	NKTR-214	Nektar Therapeutics, San Francisco, CA, U.S.A.	I/II/III
RO6874281	Hoffmann–La Roche, Basel, Switzerland	I/II
THOR-707	Synthorx, La Jolla, CA, U.S.A.	I/II
Arginase inhibitors	CB-1158	Incyte Corporation, Wilmington, DE, U.S.A.	I/II
Oncolytic peptides	LTX-315	Lytix Biopharma, Oslo, Norway	II
Interleukin 10	AM0010 (pegilodecakin)	Eli Lilly and Company, Indianapolis, IN, U.S.A.	I/II

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Poly-ICLC = polyinosinic-polycytidylic acid–poly–L-lysine carboxymethylcellulose.

Modulating and Predicting Immune Toxicity for Better Efficacy

Immunotherapies are often limited by their immune-related adverse events (iraes), an immune activation and inflammatory response against the host’s healthy tissues. Immune activation against the host’s tumour is the desired outcome, but iraes are challenging to predict, diagnose, and treat. In the setting of metastatic melanoma, the addition of a ctla-4 antibody to PD-1 blockade is associated with only an incremental increase in survival, but at the cost of more than double the rate of serious iraes9. A recent meta-analysis reported a fatality rate of up to 1 patient in every 77 treated using an ici combination10. For specific iraes, such as immune-related myocarditis, the mortality rate is as high as 50% in treated patients11. Numerous predictors of iraes have been proposed (baseline lymphopenia and eosinophilia, B cell changes, T cell repertoire, circulating il-17, and gut microbiota changes12–17), but few have been prospectively validated.

For serious iraes, guidelines recommend broad immunosuppression consisting of corticosteroids, followed by one or more biologics (tumour necrosis factor inhibitors) or T cell suppressants (such as mycophenolate mofetil)18–20. Very little prospective knowledge has been developed about the consequences of those therapies for cancer-related outcomes. An analysis of the baseline use of corticosteroids in patients with lung cancer reported an association with worse survival outcomes21. Similarly, the use of high-dose steroids in the setting of immune-related hypophysitis in patients with metastatic melanoma was also associated with worse survival22. On the other hand, the use of corticosteroids in other clinical settings in which patients experience iraes was not associated with a reduced response to ici therapy or with survival23. More studies are needed to assess the optimal immunosuppression regimen to be used with icis to avoid impairing their efficacy. The use of mtor (mechanistic target of rapamycin) inhibitors shows promise to abate toxicities without impairing ici efficacy in the specific setting of organ transplantation24–26.

Modulating cytokines in the setting of an ici is a dualedged sword. Many of those soluble factors, such as tumour necrosis factor α and il-17, are called “pleiotropic cytokines” for the dual roles they play in immunity: on the one hand, they promote tumour surveillance; on the other hand, they can be key mediators of autoimmune reactions. As discussed earlier, circulating il-17 is a biomarker for the prediction of ici-induced colitis16. The addition of the il-17 monoclonal antibody secukinumab for the treatment of immune-related colitis and psoriasis, while effective at abating immune toxicities, has been reported to induce tumour escape27. The same effect has not yet been reported for tumour necrosis factor α or il-6. Tumour necrosis factor blockade seems not only to be safe for the treatment of ici-related colitis, but in animal models of melanoma, also adds synergistic antitumour efficacy to PD-1 inhibition28,29. Those early observations collectively highlight the importance of further study of the role of various cytokines and immune cells in the pathogenesis of iraes.

A New Era for Tumour-Specific Vaccines in Combination with ICIs

Despite promising results with icis, single-agent PD-1 inhibitor has an objective response rate that varies from almost nonexistent in pancreatic cancer and microsatellite-stable colonic adenocarcinoma, to an average of 15%–30% in most other tumour types, but 50%–80% in melanoma, Hodgkin lymphoma, squamous-cell carcinoma of the skin, and Merkel cell carcinoma. The addition of an anti–ctla-4 agent increases the response rate, but comes with a significantly higher toxicity rate. A rational approach to achieving a higher response rate without increasing autoimmunity has been to combine an ici with a therapy that can sensitize the host’s immune system to the tumour in advance. Recent studies have shown that personalized neoantigen-based tumour-specific vaccines hold considerable promise.

Unlike hematologic malignancies, in which a common antigen is uniformly expressed on the surface of all malignant cells, making them amenable to targeted therapies such as therapy with chimeric antigen receptor T cells, solid tumours either lack such an antigen or undergo mutations under natural selection when exposed to therapeutic interventions such as monoclonal antibodies. Traditional cancer vaccines have failed for a number of potential reasons, including improper selection of a target antigen, lack of immunogenicity, or inadequate patient selection. In the new era of cancer vaccines, efficacy relies on computational pipelines geared to identify personal candidate neoantigens in real time. Comprehensive mutation analysis is performed by whole-exome sequencing, and based on affinity predictions, neo-epitopes encoded by somatic mutations in the tumour are selected given their probability of being presented by the individual’s major histocompatibility class molecules30–34. One of the most commonly used prediction algorithms for major histocompatibility class i binding, NetMHCpan (DTU Health Tech, Technical University of Denmark, Kongens Lyngby, Denmark), relies on state-of-the-art neural networks, putting the spotlight on the current power of bioinformatics for guiding precision immuno-oncology35. The concept has been translated to multiple phase i clinical trials eval‎uating neoantigen-based vaccines36–38. Other clinical trials are testing this novel vaccination strategy in combination with ipilimumab (NCT02950766 at https://ClinicalTrials.gov/) or nivolumab (NCT02897765), or as a personalized messenger rna mutatome vaccine in combination with the PD-L1 inhibitor atezolizumab (NCT03289962).

The Crucial Role of the Tumour Microenvironment

An important advance in the field of immuno-oncology came from the increased understanding of the crucial role of the tumour microenvironment in the modulation of anticancer immune responses. In colorectal cancers, immune cell infiltration into the tumour microenvironment has been correlated with a strong immune response to treatment with icis, with even better correlation than for microsatellite instability39,40. Based on those findings, the concept of “immune contexture” has been proposed and validated, with tumours classified into four proposed categories (hot, excluded, immunosuppressed, and cold)41,42. Apart from the presence of tumour-infiltrating lymphocytes, additional features such as the expression‎ of anti–PD-L1 on tumour-associated immune cells, genomic instability, and the presence of a pre-existing antitumour immune response have been described as characteristics of “hot” tumours, which are associated with a good response to icis43. Conversely, apart from being poorly infiltrated, “cold” tumours have also been described to be immunologically “ignorant” (scarcely expressing PD-L1) and characterized by high proliferation with a low mutational burden (low expression‎ of neoantigens) and by low expression‎ of antigen presentation machinery markers such as major histocompatibility class i43. Transforming “cold” tumours into fertile “hot” tumours responsive to icis is an active area of investigation.

Radiotherapy and chemotherapy have both been used in combination with icis to increase the antigenicity and priming potential of tumours, which in turn could be applied to turn “cold” tumours into “hot” ones. Ionizing radiation–induced immunogenic cell death and antigen release could potentially turn tumour cells into an in situ vaccine44. The outcome of that approach is not only local tumour control, but possibly a response at distant tumour sites through the abscopal effect45. On the other hand, chemotherapy can induce mutations, leading to the generation of neo-epitopes and therefore increasing the antigenicity of tumours46. Other approaches with proven benefit have been the local injection of oncolytic viruses into tumour beds. These native or genetically modified viruses selectively infect and replicate within tumour cells, eventually leading to tumour cell lysis and antigen release47. Again, that process results in local priming of the immune system, with responses seen both locally and systemically. The effect is accentuated when those therapies are combined with icis48.

Another key targetable characteristic of “cold” tumours is strong expression‎ of mesenchymal and collagen barrier molecules that prevent the migration of tumour-infiltrating lymphocytes to the tumour bed49,50. As an example, inhibition of transforming growth factor β, a key player in the formation of the mesenchymal barrier, when combined with an ici resulted in a strong antitumour response in mouse models51. That approach is now being tested in clinical trials.

Finally, another strategy that can convert a “cold” to a “hot” tumour microenvironment uses inhibitors of oncogenic kinases (reviewed in Guo et al.52). The pi3k/akt pathway, glycogen synthase kinase 3α/β, and Mnk1 and Mnk2 are often aberrantly activated in cancer, and appreciation for their tumour-extrinsic effects in the cells of the tumour microenvironment to promote immune suppression is growing. For example, Mnk1 and Mnk2, which are critical regulators of messenger rna translation, have important immunomodulatory antitumor effects. Inhibitors of Mnk1 and Mnk2 can block the expression‎ of secreted factors such as Nodal and Angptl453,54, inhibiting the survival of neutrophils55 and suppressing the expression‎ of PD-L156. The Mnk1 and Mnk2 inhibitors are actively being pursued in the clinic (see NCT04261218, NCT03616834, and NCT03258398 at https://ClinicalTrials.gov/).

Targeting Tumour Metabolism in the Tumour Microenvironment

There is growing evidence that the tumour microenvironment supports inappropriate metabolic reprogramming, negatively affecting T cell function and resulting in attenuated antitumour immune responses57,58. In that context, targeting both tumour and T cell metabolism can beneficially enhance immunity in an inhospitable microenvironment and markedly improve the success of immunotherapies. As discussed earlier, tils in the tumour microenvironment have significant prognostic and predictive significance. Their function is limited not only by immune checkpoints, but also by increasingly recognized “metabolic checkpoints”59.

Rapidly dividing tumour cells show complex and dynamic metabolic reprogramming and high glycolytic activity, a phenomenon called the “Warburg effect,” which is recognized as one of the hallmarks of carcinogenesis60. Thus, tumour cells impede the access of T cells to nutrients necessary for their activation and generate high levels of lactate. The resulting scarcity of nutrients and accumulation of metabolic waste products in the tumour microenvironment lead to a til metabolic switch that impairs optimal proliferation and function61.

Recent evidence suggests that icis might directly sculpt the metabolic landscape in the tumour microenvironment, thus affecting the functioning of effector T cells. On the one hand, ctla-4 and PD-1 binding to their respective ligands impairs the metabolic til phenotype by inhibiting glycolysis62, thus causing reduced cytokine secretion and leading to an exhausted effector T cell phenotype63. On the other hand, icis also have the opposite effect on metabolic reprogramming of cancer cells. Ligation of PD-L1 directly upregulates glycolysis in cancer cells by promoting glucose uptake and production of lactate, thus promoting tumour growth and metastasis64,65. Many therapeutic strategies have been proposed to tackle that imbalance.

The pi3k/akt/mtor pathway is well known to play a critical role in integrating the metabolism signals of cancer and immune cells. Recent preclinical evidence suggests that rapamycin, in combination with icis, augments cytotoxic and memory T cell function24,66. Another promising therapeutic is metformin in combination with icis. Metformin is known to target the mitochondrial respiratory complex i and to activate ampk pathway signal transduction, a key pathway in T cell regulatory and metabolic functioning67,68. In a cohort of patients with metastatic melanoma who received metformin in combination with icis, favourable treatment-related outcomes (objective response rate, disease control rate, median progression-free survival, and median overall survival) were observed69. Those findings await further validation in larger randomized studies.

Besides glycolysis, another key element of metabolism dictating immune function in the tumour microenvironment is amino-acid catabolism. It is well established that l-arginine, tryptophan (Trp), and glutamine play fundamental roles in tumour progression and immunity70. Targeting those amino acids and their metabolic pathways in cancer therapy therefore becomes a promising strategy for the development of novel therapeutic agents. As one example, the depletion of tryptophan and the increase in kynurenine (Kyn) exert an important immunosuppressive function by activating T regulatory cells and suppressing the functioning of effector T cells71. The catabolic ido1 enzyme in the Trp–Kyn–AhR metabolic pathway thus became an interesting therapeutic target. Despite promising results in early-phase clinical trials in a range of tumour types, a phase iii study of the ido1-selective inhibitor epacadostat in combination with pembrolizumab in metastatic melanoma showed no difference between the epacadostat–pembrolizumab group and the placebo–pembrolizumab group72. That resulted in a diminution of interest in ido1 inhibitors; however, other approaches to inhibiting that pathway continue to be considered. Novel Trp–Kyn–AhR pathway inhibitors such as Kyn-degrading enzymes, direct AhR antagonists, and Trp mimetics are advancing in early-stage or preclinical development73. Despite the uncertainty surrounding ido1 inhibition, ample preclinical evidence supports the continued development of Trp–Kyn–AhR pathway inhibitors to enhance ici efficacy.

The Microbiome As a Master Regulator of Both ICI Efficacy and Toxicity

The host microbiome plays an important role in the efficacy of vaccine immune responses74, the promotion of carcinogenesis75–81, and the efficacy and toxicity of anticancer treatments82–84, including icis82,85. A foundational study in mice showed that manipulation of the baseline flora of the gut microbiome affects melanoma growth kinetics and can enhance ici efficacy86. Other preclinical studies showed that the efficacy of anti–ctla-4 therapy can be compromised by antibiotic-induced dysbiosis or use of germ-free mice87. The efficacy of the ici could be restored in antibiotic-treated mice after gavage with Bacteroides fragilis or Bacteroides thetaiotaomicron (order Burkholderiales), or both, through an enhanced il-12–dependent type 1 T helper immune response87. Furthermore, analysis of stool from patients with ipilimumab-treated melanoma demonstrated selective enrichment of B. fragilis in clinical responders, possibly suggesting the presence of a ctla-4 blockade–induced gut dysbiosis.

Other key studies have focused on identifying human microbiota signatures predictive of clinical ici responses88–92. Patients with metastatic melanoma who were responders to anti–PD-1 therapy were shown to have enrichment of Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium in pre-treatment stool samples89. Subsequent fecal microbiota transplantation (fmt) of “responder” gut flora into germ-free mice was associated with improved melanoma tumour control through a CD8+ T cell immune response89. Furthermore, the ratio of “beneficial” to “non-beneficial” bacteria species in patients was the best predictor of an antitumour clinical response89. Another group identified enrichment of Akkermansia muciniphila in the microbiota of responders to anti–PD-1 or PD-L1 icis in 3 cancer subtypes. They further demonstrated that oral supplementation with A. muciniphila, Alistipes indistinctus, or Enterococcus hirae could restore ici antitumour efficacy in germ-free mice colonized with bacterial species from non-responder fmt88. A third fundamental study showed that patients with melanoma responding to ici had greater alpha diversity in their gut flora, with selective enrichment in order Clostridiales family Ruminococcaceae, especially genus Faecalibacterium90. On the other hand, the microbiomes in ici non-responders showed a shift toward order Bacteroidales. Taken together, those studies demonstrate that the antitumour immune response depends on the composition of the gut microbiome and that antibiotic-induced dysbiosis is associated with reduced immune priming and primary resistance to immunotherapy. The deleterious effect of antibiotics given close to the time of ici treatment was confirmed in retrospective analyses of ici-treated patients with various cancers (renal cancer, non-small-cell lung cancer, urothelial cancer, and melanoma) 88,93–95. Thus far, a modest overlap in key microbiome mediators of response to anti–PD-1 or PD-L1 therapies has been observed across cohorts, with an apparent common responder signature enriched in A. muciniphila, Clostridiales, E. faecium, Eubacterium species, the Firmicutes, and Ruminococcus species96. Although poor overlap between study cohorts might be a result of differences in technique or tumour type, additional heterogeneity of the gut microbiome linked to genetics, geography, lifestyle, or prior antibiotic and other drug exposure must be considered. Ultimately, “responder” gut profiles will likely reflect combinations of taxonomic orders and families rather than the presence or absence of one or a few particular species.

Besides priming the immune response to icis, the microbiome also modulates iraes17,91. For instance, metagenomic sequencing found members of the Bacteroidetes phylum (families Bacteroidaceae, Rikenellaceae, and Barnesiellaceae) to be more abundant in stools obtained before treatment from patients with melanoma who did not develop ipilimumab-induced colitis, implying a protective effect of those microorganisms17. Importantly, specific microbial metabolic pathways (polyamine transport and vitamin B synthesis) were found to be predictive of resistance to ctla-4 blockade–induced colitis17. Another group corroborated the protective effect of a Bacteroidetes-rich phylotype against ctla-4 blockade–induced colitis in patients with melanoma. They further demonstrated that favourable clinical responses and susceptibility to colitis were both correlated with baseline microbiota enrichment in phylum Firmicutes (unclassified Ruminococcaceae, Clostridium cluster XIVa, and Blautia) and, in particular, Faecalibacterium, which is known to exert an anti-inflammatory role in the gut91. Further, the resolution of refractory ici-associated colitis in 2 patients with cancer was achieved by fmt from a healthy donor97. Thus, a critical goal of microbiome manipulation is to disentangle the modulation of toxicity from the preservation or enhancement of ici efficacy98.

There is a strong push to translate those newly acquired basic science findings about the microbiota into therapeutic clinical tools. Several trials are eval‎uating safety, efficacy, and immune profile changes in patients with ici-resistant cancer treated with “complete responder” fmt (see NCT03353402, NCT03341143, and NCT03637803 at https://ClinicalTrials.gov/). The safety of fmt is particularly important and under scrutiny, given that fmt or bacterial colonization experiments in mice have revealed a potential for transfer of chronic diseases99,100 or increased risk of tumorigenesis76,101. Probiotics—loosely defined as health-promoting live organisms or fermented foods—are so far being assessed mostly in clinical trials aiming to reduce anticancer treatment toxicities; only one registered trial is testing their efficacy in the context of icis (NCT03829111). The optimal probiotic cocktail for immunotherapy remains to be determined and might vary with the ici or the tumour type. Additionally, reliable preparation of probiotics will be essential, likely requiring changes to their regulation. Ultimately, clinical studies of the effects of the microbiome on ici efficacy or toxicity will have to consider other confounding factors known to affect the commensal microbiome, such as concomitant radiation therapy102, exposure to antibiotics or other drugs (proton-pump inhibitors, antipsychotics, antimetabolites) 103, and diet (including method and composition).

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SUMMARY

Cancer immunotherapy has dramatically changed survival and quality of life for patients. However, not all cancers are equal, and very few predictors of response and toxicity currently exist. Despite the rapid advances made in the field, immuno-oncology is still in its relative infancy, with numerous challenges and hurdles yet to be overcome. Over time, a realization grew that the standard tools used to assess choice of treatments in the era of chemotherapy and targeted therapies might not be valid for the new immunotherapies. As an example, the Response Eval‎uation Criteria in Solid Tumors (recist) used to assess response to treatments were modified to create irecist, which accounts for the novel patterns of response seen during immunotherapy, including tumour pseudoprogression104. In the same way that TNM staging has been crucial in guiding treatments in the era of chemotherapy, novel tools are required in the era of cancer immunotherapy. The Immunoscore has already been validated as adding important prognostic information to TNM staging in colon cancer39. The fact that T cells are currently widely recognized as the key mediators of antitumour efficacy with ici treatment suggests that use of the Immunoscore is an attractive option to help guide treatment selection in other cancer types as well. Still, that option does not exclude the possible use of additional parameters that might provide further insights into the specifics of each case.

It is becoming more challenging to increase the efficacy of combination therapies already established in clinical practice. In metastatic melanoma, combined ctla-4 and PD-1 blockade has achieved an unprecedented five-year overall survival above 50%105. In metastatic renal cell carcinoma, the same combination has been associated with an overall survival rate exceeding 60% at 3 years in the intention-to-treat population106,107. In the large landscape of ongoing early-phase clinical trials, few novel combinations have achieved a level of efficacy rivalling those new standards of care. What certainly remains to be improved is their safety profiles.

The approved induction and regimen dose of combination icis (ipilimumab 3 mg/kg and nivolumab 1 mg/kg every 3 weeks) in the setting of melanoma is associated with a 59% rate of grades 3–4 toxicities108. Preliminary results from CheckMate 511, which used alternative dosing (ipilimumab 1 mg/kg and nivolumab 3 mg/kg every 3 weeks), showed a significant improvement in toxicity without loss of efficacy109. Given that iraes can sometimes be associated with mortality and significant lifelong morbidity (for example, de novo insulin-dependent diabetes, persistent pituitary dysfunction, or immune-related inflammatory arthropathies), predictors and novel strategies to abate those toxicities are urgently needed.

Another area of urgent need is to find novel treatments both for patients who are primary non-responders to icis and for those who develop secondary resistance to those therapies. Beyond ici failure, very few treatments have been studied, and physicians often rely on previously validated standards of care for each specific cancer. Early observational data suggest that exposure to icis might modulate the response to standard treatments received after progression. For instance, exceptionally high response rates to chemotherapy have occasionally been documented after ici failure110,111. Those observations might be secondary to immunotherapy having removed the inhibition initially exerted by tumour cells or other immune cells, followed by cytotoxic chemotherapy–mediated killing of tumour cells. On the other hand, progression-free survival and the adverse event profiles associated with exposure to targeted therapies (such as braf inhibition in melanoma) might be adversely affected by first-line exposure to icis112.

To summarize, the future of cancer immunotherapy could rely on combination therapies using checkpoint inhibitors not with other novel checkpoint inhibitors, but rather with personalized cancer vaccines and novel targeted therapies directed at the tumour microenvironment, tumour glycosylation, and the host microbiome, as outlined in the present review. Advances in those fields will allow movement away from the current broad “shotgun” approach, which exposes all comers within the approved indications to icis, to treatments tailored to the factors that make each cancer and host a unique pairing.

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Footnotes

CONFLICT OF INTEREST DISCLOSURES

We have read and understood Current Oncology’s policy on disclosing conflicts of interest, and we declare the following interests: WHM reports personal fees from Bristol–Myers Squibb, Merck, Roche, Novartis, and Amgen outside the submitted work; and KE reports personal fees from Bristol–Myers Squibb outside the submitted work. LR and NB have no conflicts of interest to disclose.

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