Supportive Care in Cancer

https://doi.org/10.1007/s00520-020-05705-5

SPECIAL ARTICLE

Cancer immunotherapy–related adverse events:

causes and challenges
Ada G. Blidner 1 & Jennifer Choi 2 & Tim Cooksley 3 & Michael Dougan 4 & Ilya Glezerman 5 & Pamela Ginex 6 &
Monica Girotra 7,8 & Dipti Gupta 8 & Douglas Johnson 9 & Vickie R. Shannon 10 & Maria Suarez-Almazor 11 &
Bernardo L. Rapoport 12,13 & Ronald Anderson 13

Received: 21 April 2020 / Accepted: 20 August 2020

# Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract
Despite the success and ongoing promise of monoclonal antibody–targeted immune checkpoint inhibitor immunotherapy of
advanced malignancies, in particular, antibodies directed against CTLA-4 and PD-1/PD-L1, the development of immune-related
adverse events (irAEs) remains a constraint of this type of therapy. Although rarely fatal, the occurrence of irAEs may necessitate
discontinuation of immunotherapy, as well as administration of corticosteroids or other immunosuppressive therapies that may
not only compromise efficacy but also predispose for development of opportunistic infection. Clearly, retention of efficacy of
immune checkpoint–targeted therapies with concurrent attenuation of immune-mediated toxicity represents a formidable chal-
lenge. In this context, the current brief review examines mechanistic relationships between these events, as well as recent insights
into immunopathogenesis, and strategies which may contribute to resolving this issue. These sections are preceded by brief
overviews of the discovery and functions of CTLA-4 and PD-1, as well as the chronology of the development of immunother-
apeutic monoclonal antibodies which target these immune checkpoint inhibitors.

Keywords Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) . Ipilimumab . Microbiome . Nivolumab . Programmed cell
death protein 1 (PD-1) . Regulatory T lymphocytes (Tregs)

Introduction the treatment of malignant disease to have occurred during the

past several decades. This has resulted from major advances
The relatively recent renaissance of cancer immunotherapy and innovations in immunological and biomolecular technol-
undoubtedly represents the most significant development in ogies. These, in turn, have led to the unravelling of various

* Bernardo L. Rapoport Monica Girotra

[email protected] [email protected]

Ada G. Blidner Dipti Gupta

[email protected] [email protected]

Jennifer Choi Douglas Johnson

[email protected] [email protected]
Tim Cooksley Vickie R. Shannon
[email protected] [email protected]
Michael Dougan
Maria Suarez-Almazor
[email protected]
[email protected]
Ilya Glezerman
[email protected] Ronald Anderson
[email protected]
Pamela Ginex
[email protected] Extended author information available on the last page of the article
 Support Care Cancer

mechanisms of immune regulation, many of which can be Although this type of immunotherapy proved successful in
exploited by tumors, enabling their growth and spread. With only 20–30% of patients, most of these showed long-term
respect to the impact on the immunotherapy of cancer, the positive responses, previously unthinkable for advanced
discovery of two members of a family of immunoregulatory melanoma.
proteins, known as immune checkpoint inhibitors (ICIs), rep-
resents the most significant development to date. These pro-
teins, known as CTLA-4 (cytotoxic T-lymphocyte-associated PD-1/PD-L1
protein 4) and PD-1 (programmed cell death protein-1) and its
ligands, PD-L1 and PD-L2, discovered in the early-to-mid- Subsequently, the PD-1/PD-L1/PD-L2 axis became the most
1990s, are recognized as being intimately involved in sup- studied immune checkpoint system in the onco-immunology
pressing anti-tumor immune responses [1, 2]. field. The PD-1 receptor was discovered by Dr. Tasuku Honjo
in the 1990s [2]. As the name implies, PD-1 plays a crucial
role in promoting programmed death of lymphocytes.
CTLA-4 However, only after the successful genetic engineering of
PD-1 gene knockout murine models, which resulted in the
In 1987, the co-inhibitory receptor, CTLA-4, was cloned [3]. development of a lupus-like syndrome, was the involvement
This molecule is a protein, which competes with the co- of PD-1 in immune regulation revealed [9]. Later, in collabo-
stimulatory signaling molecule, CD28, expressed on effector ration with Dr. Honjo’s research team, Dr. Arlene Sharpe and
T cells for the activation ligands, CD80/CD86 (also known as Dr. Gordon Freeman discovered that the PD-1 ligands, PD-L1
B7.1/B7.2), expressed on antigen-presenting cells (APCs, pre- and PD-L2, were expressed on tumor cells, corroborating the
dominantly dendritic cells, as well as macrophages). role of the PD-1/PD-L1/PD-L2 axis in suppressing anti-tumor
Importantly, the binding affinity of CTLA-4 for immunity [10].
CD80/CD86 is approximately 100 times higher than that of Like CTLA-4, PD-1 is expressed on Tregs, as well as
CD28, effectively suppressing antigen-activated T cell recep- on effector T cells, following sustained, antigen-driven T
tor (TCR) signaling, preventing T cell activation [4]. During cell activation, as an additional mechanism to control the
the course of an immune response, activated T cells express reactivity of these cells. This immunosuppressive mecha-
increasing levels of CTLA-4 as a result of sustained activation nism was first described in the setting of chronic viral
due to constant antigen exposure. This scenario is normal in infections and later in cancer [11]. Importantly, the PD-1
chronic infections and cancer to prevent over-reactivity of ligand, PD-L1, is expressed on APCs, cancer cells, and
immune responses [5]. In this context, the crucial role of endothelial cells, while PD-L2 is mainly restricted to
CTLA-4 in immune regulation has been convincingly demon- APCs, although it may also be expressed on tumor cells.
strated in gene knockout mice, in which ablation of CTLA-4 Contact between PD-1 and its ligands activates signals
resulted in the development of a lethal lymphoproliferative which suppress T cell priming and proliferation [12]. In
disorder [6]. this context, blockade of PD-1/PD-L1 enhances anti-
In addition to effector CD4 and CD8 T cells, which express tumor immunity by reactivating dysfunctional CD4 and
CTLA-4 following antigen stimulation, another T cell popu- CD8 tumor-specific T cells [13].
lation, known as regulatory T cells (Tregs), constitutively Although the development of CTLA-4-targeted strategies
(spontaneously) express high levels of CTLA-4, enabling triggered the revival in anti-cancer immunotherapy, monoclo-
these cells to effectively suppress immune responses [7]. nal antibody–based blockade of PD-1 has become the most
Although Tregs are particularly important in preventing the prominent type of immunotherapeutic anti-cancer modality,
development of autoimmune and autoinflammatory disorders, administered either alone or in combination with other thera-
over-activity of these cells poses the risk of development of peutic strategies. In 2014, mAb-based PD-1 blockade was
cancer and infection. In the setting of cancer, blockade of approved for the treatment of advanced melanoma. One year
CTLA-4 enhances anti-tumor immunity not only by releasing later, as a result of convincing clinical trial data, PD-1-targeted
the brakes on anti-tumor effector T cells but, perhaps more monoclonal antibody–based therapy was approved for non-
importantly, by attenuating the potent regulatory functions of small cell lung cancer and renal cell carcinoma. Later, in
Tregs [8]. 2016, head and neck cancers and Hodgkin’s lymphoma were
Following promising results in pre-clinical and clinical tri- added to the list of approvals, while in 2017, the list was
als, originating from the pioneering work of Dr. James extended to include urothelial carcinoma and all solid tumors
Allison´s team at the MD Anderson Cancer Center, the Food with DNA repair machinery deficiencies. In the case of PD-
and Drug Administration (FDA) of the USA approved the L1-neutralizing monoclonal antibodies, these were approved
therapeutic application of neutralizing monoclonal antibodies for the treatment of urothelial and bladder cancer as well as
(mAbs) against CTLA-4 for metastatic melanoma in 2011. some forms of lung tumors in 2016 [14].
Support Care Cancer

Immunotherapeutic targeting of CTLA-4 Intriguingly, although incompletely understood, an in-

and PD-1/PD-L1 creasing number of studies, both pre-clinical and clinical, have
linked alterations in immune homeostasis in the gastrointesti-
Predictably, and as mentioned in the preceding sections of nal tract (GIT), which accommodates large numbers of Tregs
this review, recognition of the key involvement of CTLA-4 [19], to both the clinical efficacy and immune-mediated tox-
and PD-1 (as well as its ligands, PD-L1 in particular, and icities of ICI-targeted mAbs [20]. In this context, a broad
PD-L2) triggered the pursuit of safe and effective strategies expansion of gut-associated, pro-inflammatory CD4+ Th17
to counter the immunosuppressive activities of these cells, with both anti-tumor and autoimmune/
checkpoints in the setting of treatment of advanced malig- autoinflammatory potential, represents a potential mechanism
nant disease. This ambition has been realized through in- of ICI therapy-associated irAEs [21]. Indeed, the recent iden-
novations in mAb technology, which have enabled the de- tification of the involvement of commensal bacteria of the gut
sign and production of mAbs, such as ipilimumab and microbiome as prominent determinants of the anti-cancer ef-
nivolumab/pembrolizumab, both fully human mAbs, of ficacy of ICI-targeted mAbs is in keeping with the role of the
the immunoglobulin G1 (IgG1) and IgG4 isotypes, which gut-associated immune system in driving anti-tumor immuni-
target CTLA-4 and PD-1, respectively [15]. Now widely ty, as well as the pathogenesis of some types of irAEs [22, 23];
used in the treatment of different types of metastatic dis- moreover, different species of bacteria have recently been cor-
ease, the clinical application of these ICI-targeted mAbs related with responses to anti-CTLA-4 and anti-PD-1 thera-
does, however, necessitate close monitoring of patients pies [24]. Potential, albeit unproven, mechanisms underpin-
due to the potential for development of a spectrum of side ning this relationship include the following:
effects known as immune-related adverse events (irAEs)
[16, 17]. As described extensively in the accompanying arti- & Attenuation of immune constraints imposed by Tregs re-
cles in this issue of the “Journal,” irAEs affect all major organs sults in immune recognition of gut commensal organisms,
and may present as newly diagnosed disorders, or less com- thereby priming dendritic cells for antigen presentation
monly as exacerbations of pre-existing autoimmune/auto- and activation of CD4+ and CD8+ effector cells reactive
inflammatory diseases. with commensal-derived antigens that are cross-reactive
The development of irAEs associated with ICI-targeted with tumor antigens and/or autoantigens [25].
immunotherapy results from attenuation of CTLA-4-/PD-1- & Notwithstanding diminished reactivity of Tregs, certain
mediated immunoregulatory constraints, leading to a broadly types of gut commensal bacteria appear to be critically
over-reactive immune system. The immunopathogenesis and involved in the priming of a subset of intestinal dendritic
prevention of irAEs represent the remaining focus of this brief cells necessary for activation and expansion of Th17 cells,
review. which have the potential to migrate to distant anatomical
sites [26].

Mechanisms underpinning the development Irrespective of which of these, or any other mechanisms,
of immunotherapy-related IrAEs are operative in the setting of ICI mAb-mediated anti-can-
cer immunotherapy, disentangling therapeutic activity
Administration of ICI-targeted mAbs results in the reactiva- from development of irAEs clearly represents a very chal-
tion of dysfunctional adaptive and innate immunity, which lenging prospect, which may necessitate manipulation of
may encompass beneficial therapeutic effects on the anti- the gut microbiome [26–28], a strategy that is being stud-
tumor response. On the downside, however, over-reactivity ied in a myriad of clinical trials [24]. Additional, albeit
of the immune system also predisposes for development of largely unexplored, approaches include attenuation of the
irAEs. pro-inflammatory activities of Th17 cells. This may be
This contention is supported by a spate of recent publica- achieved by the administration of monoclonal antibodies
tions highlighting the strong correlation between the anti- that target cytokines which drive expansion of Th17 cells,
cancer therapeutic efficacy of ICI-mediated immunotherapy specifically interleukin(IL)-1β, IL-6, IL-23, as well as
and the frequency and severity of irAEs [reviewed in 18]. those that directly target IL-17 or its receptor [18, 29].
Mechanisms underpinning the immunopathogenesis of Alternatively, strategies which increase the therapeutic ef-
irAEs are likely to be multifaceted, encompassing hyperacti- ficacy of ICI-based immunotherapy may also enable short-
vation of B cells and augmentation of autoantibody produc- ening of the duration of treatment, which, in turn, may
tion in diseases such as myasthenia gravis, autoimmune he- attenuate the development of irAEs. Such strategies in-
molytic anemia, and type 1 diabetes mellitus, while others clude identification of biomarkers of treatment efficacy,
such as rheumatoid arthritis, colitis, and multiple sclerosis as well as those which augment the anti-tumor efficacy of
are predominantly T cell–driven disorders. ICI-targeted mAbs.
 Support Care Cancer

Identification of biomarkers predictive (ii) low-level presentation of tumor antigens; and (iii)
of treatment efficacy and possible reduced increased recruitment of immunosuppressive cell popu-
risk of development of IrAEs lations and tumor-derived immunosuppressive factors
[38]. To counter these obstacles to successful immuno-
During the last 2 years, analysis of the tumor mutational bur- therapy, personalized screening tests are being devel-
den (TMB) has gained prominence, largely due to the findings oped to determine which of these mechanisms are oper-
of several clinical trials which reported good correlations be- ative in individual patients. This, in turn, may enable
tween high TMB and response to ICI-based therapy [30–32]. detection of the best combination of immunotherapies
In this context, a high tumor mutational burden translates into to improve response rates and overall survival. These
broader tumor antigenicity, resulting in a more intense infil- include (i) strategies to attenuate the influx and/or ac-
tration of immune cells to the tumor site. On the other hand, it tivities of immunosuppressive cell types, including
has been reported that broadening of tumor antigen heteroge- Tregs in particular, as well as myeloid-derived suppres-
neity compromises the efficacy of host anti-tumor immune sor cells (MDSCs) and M2-type macrophages; (ii) CAR
defenses [33, 34], possibly because the expression of fewer, (chimeric antigen receptor) T cell therapies; (iii)
more evenly distributed, tumor antigens elicits a more robust cytokine-based therapies; and (iv) combinations of dif-
and effective immune response. Clearly, additional research is ferent types of ICI-targeted mAbs [39].
necessary to accurately establish the relevance of the TMB as Another potential, possibly more practical and less
a biomarker of the efficacy of ICI-based immunotherapy. expensive, strategy is to combine ICI-based immuno-
Pre-treatment detection of PD-L1 expression on tumor therapy with inducers of immunogenic cell death, spe-
cells represents an alternative strategy to predict the potential cifically radiotherapy, targeted therapy, and selected
efficacy of PD-1-based immunotherapy. In this context, ex- chemotherapeutic agents such as anthracyclines [18].
pression of PD-L1, even at low levels, on non-small cell lung These agents potentiate localized anti-tumor immune re-
carcinomas is considered to be a useful predictor of respon- sponses via the release of damage-associated molecular
siveness to PD-1-targeted monotherapy. In addition, simulta- patterns (DAMPS) from dead and dying tumor cells, a
neous expression of PD-L1 on both tumor and infiltrating process known as immunogenic cell death, which may
immune cells in triple-negative breast and bladder cancers harmonize with ICI-based immunotherapy by stimulat-
may also be predictive of the efficacy of PD-1-based immu- ing the innate immune response [40].
notherapy [35–37]. However, the correlation between PD-L1 These various potential strategies to ameliorate the devel-
expression and response is imperfect within these tumor types, opment of irAEs in the setting of retention of efficacy of ICI-
as well as in other cancers (including renal cell carcinoma), based immunotherapy are summarized in Table 1.
indicating that measurement of PD-L1 has minimal/no predic-
tive capacity in these settings.
Conclusions

Potentiation of ICI-targeted anti-tumor ICI-based immunotherapy of cancer, either as monotherapy or

immune responses as an adjunct to radiation therapy, chemotherapy, and/or sur-
gery, will undoubtedly become a future cornerstone of oncol-
Resistance mechanisms which impair the efficacy of ogy. Refinements to current immunotherapeutic strategies,
anti-tumor immunotherapy include (i) impaired T cell however, remain a priority, specifically with respect to im-
migration and infiltration through tumor parenchyma; proved therapeutic efficacy in the setting of attenuation of

Table 1 Potential strategies to

ameliorate the development of Strategy Potential benefit
immune-related adverse events
during checkpoint inhibitor– Manipulation of the gut microbiome with Re-direction of gut-association immune responses to a
based immunotherapy in the biopharmaceuticals more favorable, selective tumor-directed phenotype
setting of retention of therapeutic Cytokine targeting of Th17 cells Attenuation of the pro-inflammatory activities of Th17
efficacy cells
Identification of biomarkers predictive of treatment Shorter duration of immunotherapy and possible lesser
efficacy probability of development of irAEs
Combination therapy with other immunotherapeutic Shorter duration of immunotherapy due to potentiation
agents or with inducers of immunogenic cell death of anti-tumor host defenses and lesser probability of
development of irAEs
Support Care Cancer

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Authors’ contributions All of the authors contributed equally to the con-
intratumoral regulatory T cells. Cancer Immunol Res 1(1):32–42.
ceptualization of the manuscript; sections on immunological mechanisms
https://doi.org/10.1158/2326-6066.CIR-13-0013
were shared equally by AGB and RA, while BLR and DBJ provided
9. Nishimura H, Nose M, Hiai H, Minato N, Honjo T (1999)
clinical input and oversight. All of the authors provided critical appraisal
Development of lupus-like autoimmune diseases by disruption of
of the manuscript and approve of its submission.
the PD-1 gene encoding an ITIM motif-carrying immunoreceptor.
Immunity 11(2):141–151. https://doi.org/10.1016/s1074-7613(00)
Funding information Professor BL Rapoport is supported by the Cancer 80089-8
Association of South Africa (CANSA) and the National Research 10. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M,
Foundation (NRF) of South Africa. Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield
Dr. I. Glezerman is supported by the NIH/NCI (Cancer Center Support EA, Bourque K, Boussiotis VA, Carter LL, Carreno BM,
Grant P30 CA008748) Malenkovich N, Nishimura H, Okazaki T, Honjo T, Sharpe AH,
Freeman GJ (2001) PD-L2 is a second ligand for PD-1 and inhibits
Compliance with ethical standards T cell activation. Nat Immunol 2(3):261–268. https://doi.org/10.
1038/85330
Conflict of interest AB, RA, JC, TC, PG, DG, and VRS have no conflict 11. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe
of interest to declare. MC reports grants from Novartis, other from AH, Freeman GJ, Ahmed R (2006) Restoring function in exhausted
Neoleukin Therapeutics, personal fees from Partner Therapeutics, person- CD8 T cells during chronic viral infection. Nature 439(7077):682–
al fees from Tillotts Pharma, and grants from Genentech, outside the 687. https://doi.org/10.1038/nature04444
submitted work. MG reports other from Bristol Myers Squibb (BMS) 12. Boussiotis VA (2016) Molecular and biochemical aspects of the
and other from AstraZeneca, outside the submitted work. IG reports other PD-1 checkpoint pathway. N Engl J Med 375(18):1767–1778.
from Pfizer Inc and personal fees from CytomX Inc, outside the submitted https://doi.org/10.1056/NEJMra1514296
work. DBJ reports other from Array Biopharma, grants and other from 13. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein
BMS, grants from Incyte, other from Jansen, other from Merck, and other I, Kobayashi SV, Linsley PS, Thompson CB, Riley JL (2005)
from Novartis, outside the submitted work. In addition, DBJ has a patent CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct
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Support Care Cancer

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tional claims in published maps and institutional affiliations.

Affiliations

Ada G. Blidner 1 & Jennifer Choi 2 & Tim Cooksley 3 & Michael Dougan 4 & Ilya Glezerman 5 & Pamela Ginex 6 &
Monica Girotra 7,8 & Dipti Gupta 8 & Douglas Johnson 9 & Vickie R. Shannon 10 & Maria Suarez-Almazor 11 &
Bernardo L. Rapoport 12,13 & Ronald Anderson 13

1 8
Laboratory of Immunopathology, Institute of Biology and Department of Medicine, Memorial Sloan Kettering Cancer Center,
Experimental Medicine-CONICET, Buenos Aires, Argentina New York, NY, USA
2 9
Division of Oncodermatology, Robert H. Lurie Comprehensive Department of Medicine, Vanderbilt University Medical Center and
Cancer Center, Northwestern University Feinberg School of Vanderbilt Ingram Cancer Center, Nashville, TN, USA
Medicine, Chicago, IL, USA 10
Department of Pulmonary Medicine, The University of Texas MD
3
The Christie & Manchester University Foundation Trust, University Anderson Cancer Center, Houston, USA
of Manchester, Manchester, UK 11
Section of Rheumatology and Clinical Immunology, University of
4
Massachusetts General Hospital, Harvard Medical School, Texas MD Anderson Cancer Center, Houston, USA
Boston, MA, USA 12
The Medical Oncology Centre of Rosebank, 129 Oxford Road,
5
Renal Service, Department of Medicine, Memorial Sloan-Kettering Saxonwold, Johannesburg 2196, South Africa
Cancer Center, New York, NY, USA 13
Department of Immunology, Faculty of Health Sciences, University
6
Oncology Nursing Society, Pittsburgh, PA, USA of Pretoria, Box 667, Pretoria, PO 0001, South Africa
7
Endocrine Division, Department of Medicine, Weill Cornell Medical
College (MG, AF), New York, NY, USA