Checkpoint immunotherapy: good forcancer therapy, bad for rheumaticdiseasesLeonard Calabrese,1 Vamsidhar Velcheti2

The goal of harnessing the immune systemto fight cancer is not new; it dates back125 years to when William Coley advo-cated that the body’s response to infec-tion could have anti-tumoural effects.1

However, decades of efforts using vaccinesand immune stimulant therapies to harnessthe immune system to fight tumours havehad limited success and at times have beenfraught with serious adverse outcomes.Recently, drugs blocking negative immunecheckpoint pathways have shown remark-able clinical activity in various solid tu-mours.2 Several agents targeting two suchnegative checkpoints, the programmeddeath-1 (PD-1) pathway (pembrolizumab,nivolumab and atezolizumab) and thecytotoxic T-lymphocyte-associated pro-tein 4 (CTLA4) (ipilimumab) are curren-tly Food and Drug Administration andEuropean Medicines Agency approved.These negative checkpoint pathways play arole in immune tolerance in normal tissuesand the activation of these pathways islargely contextual. While these therapieshave added immeasurably to the longevityof many patients with malignancies, theyhave come at a cost with the develop-ment of numerous untoward autoimmuneinflammatory conditions.

The anti-tumour mechanism for check-point inhibitor therapies is incompletelyunderstood but clearly relates to themanipulation of T-cell pathways involved incellular activation and deactivation.2 T-cellhomeostasis is a tightly choreographedprocess whereby naïve Tcells rapidly prolif-erate in a logarithmic fashion when effect-ively activated and then contract followingsuccessful defeat of the challenge. CD4T-cell activation canonically requires twosignals: a primary signal (signal 1),mediated by recognition of cognate antigenby the T-cell receptor via presentation byself-major histocompatibility complex class

II molecules on the antigen-presenting cell,and a secondary signal (signal 2), mediatedby CD28 on the T-cell, binding its ligandpartner of the B7 family on the antigen-presenting cell.3 Of vital importance to thehost is the integration of deactivating path-ways or checkpoints leading to contractionof T-cell activation (figure 1). This processinitially takes place in lymphoid organs andis triggered by the expression of CTLA4 onthe activated T-cell. The newly expressedCTLA4 competes for B7 ligands andopposes CD28 activation, negatively regu-lating T-cell responses.3 In the peripheraltissues, however, PD-1 is a negative regula-tor of T-cell activity. The PD-1 pathway canbe best understood in scenarios where acti-vated Tcells (within the context of the inte-grated immune response) are unable todefeat and eliminate an antigenic stimulus.This situation would be predicted to occurwhen the immune system is confronted bychronic replicative infections such as HIVor hepatitis C virus or within a tumouralenvironment; in such situations additionalpathways are triggered to prevent collateraldamage to the host from attacking T cells.4

The phenotype of such cells is oftenreferred to as ‘exhaustive’ as the T-cell isstill capable of effector function but is atte-nuated in capacity. CTLA4 also plays a roleon CD8 and regulatory T cells (Treg cells):it is expressed on activated CD8 T cellswhere it may suppress the activity ofT-helper cells downstream; in addition, it isinvolved in immune regulation via Tregcells as it is constitutively expressed on thiscell population.5 We as rheumatologistsneed to appreciate that these same pathwaysare interdicted with the biotherapeuticagent abatacept, a fusion protein whichincorporates CLTA4, and functions toinhibit signal 2. As a result of this inhib-ition, there is a suppressive effect onimmune activation in contrast to ipilimu-mab which blocks CTLA4 and therebyreleases an immunosuppressive checkpoint.Attendant to the success of checkpoint

inhibitor therapy are a new and wide rangeof toxicities of inflammatory nature withsome having documented autoimmunemechanisms. There have been many recentreviews of these toxicities now referredto as immune-related adverse events

(irAEs).6–8 The most common toxicitiesseen with these agents include cutaneousreactions ranging from maculopapular rashto life-threatening disorders such asSweet’s syndrome, Stevens-Johnson syn-drome and toxic epidermal necrolysis,among others. Gastrointestinal toxicity iscommon, especially diarrhoea, but a frankcolitis may occur which can be life-threatening. Endocrinopathies includingthyroid disease, adrenal insufficiency and acurious syndrome of autoimmune hypo-physitis are well reported.5–7 Each of theseorgan-based toxicities has its own inci-dence and chronology of onset in theirirAE profiles. Finally there are a myriad ofother irAEs already described involvingvarious target organs such as the centraland peripheral nervous systems, eye andpancreas.8

The fact that checkpoint therapies areassociated with these irAEs should comeas little surprise as there is a plethoraof data leading to this expectation. Thestudy of knockout models reveals thatabsence of CTLA4 is associated with ahighly lethal and rapidly progressivelymphoproliferative and autoimmune dis-order.9 In a spontaneous model of myas-thenia gravis anti-CTLA4 has beendocumented to accelerate the autoimmunedisease10 and in humans anti-CTLA4associated hypophysitis is associated withanti-pituitary antibodies believed tomediate gland destruction.10 Geneticknockouts of PD-1 produce a milder auto-immune diathesis; in addition, at least onestrain of mouse develops a lupus-likediathesis when PD-1 is genetically dis-rupted.11 From a population health per-spective, CTLA4 gene polymorphismshave been associated with an increased riskof numerous autoimmune diseases in-cluding rheumatoid arthritis.12 Additionalevidence of the role of CTLA4 in con-trol of autoimmunity stems from recentelucidation of an emerging autoimmunesyndrome with multi-organ involve-ment associated with haploinsufficiency ofCTLA4, indicating that a less than normalexpression of this critical control receptorcan lead to clinical immune dysregula-tion.13 Finally, in regard to the PD-1pathway, recent studies have demonstratedthat CD8 T-cell exhaustion, a state charac-terised by increased PD-1 expression, isassociated with a favourable outcome inautoimmune disease and thus it could bereasoned that loss of this state could exacer-bate disease progression in individuals withconcomitant autoimmunity.14

In this issue of the Annals the groupfrom Johns Hopkins elegantly documents,in the first comprehensive clinical report,

1Department of Rheumatology/Immunology, ClevelandClinic, Cleveland, Ohio, USA; 2Department ofHematology and Oncology, Cleveland Clinic, Cleveland,Ohio, USA

Correspondence to Dr Leonard Calabrese,Department of Rheumatology/Immunology, ClevelandClinic, 9500 Euclid Drive, Cleveland, OH 44106, USA;calabrl@ccf.org

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the growing spectrum of complex and attimes severe rheumatic complaints occur-ring secondary to checkpoint therapies.15

Prior to this report, rheumatic complica-tions have largely been described in

isolated cases; no previous series has exam-ined these irAEs in a systematic fashion.Compared with the more common irAEs,as outlined above, we have little data onthe true incidence or on the relationship

of such rheumatic complications withdose, duration or type of therapy (ie, anti-CTLA4 vs anti-PD1 vs combinationtherapy) and unfortunately the design ofthe present study limits any insights into

Figure 1 Illustrations showing theT-cell activation, checkpoint inhibitionand enhanced anti-tumoural response.(A) Two signal bases for effective T cellactivation are shown. (B) CTLA4mediates inhibition of T-cell activationin central lymphoid compartment andPD-1/PD-L1 or L2 mediates inhibitionin peripheral tissues inducing anattenuated phenotype referred to as‘immunologic exhaustion’ as thesecells have reduced capacity for effectorfunctions such as cytotoxicity andability to promote inflammation. Thesenodes of immunologic control systemsare referred to as checkpoints andserve to protect the host fromunbridled immune activation,inflammation and autoimmunity andare attended by dampenedanti-tumoural responses. (C) Oninhibiting immunologic checkpointswith immune-based therapies such asanti-CTLA4 or anti-PD-1 or anti-PD-L1,reactivated T cells emigrate fromlymphoid compartments to seek outand engage tumours. In peripheraltissues, exhausted T cells are energisedto return to a more active effectorphenotype with enhancedanti-tumoural response but at a priceof being more proinflammatory andcapable of participating inautoimmune and auto-inflammatoryreactions. CTLA4, cytotoxicT-lymphocyte-associated protein 4;MHC, major histocompatibilitycomplex; PD-1, programmed death-1;PD-L1, programmed death ligand 1;TCR, T-cell receptor.

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these unanswered questions. Such dataare available for the more commontoxicities6–8 and the oncology communityis becoming increasingly familiar with theidentification and management of many ofthe irAEs. The very important question ofwhether checkpoint therapy exacerbatespre-existing autoimmunity is also poorlyaddressed, though limited data suggest thatthis phenomenon may occur in up to 40%of patients.16 Finally, with regard totherapy, we are also only at the beginningof understanding the optimal regimensand implications of adjunctive immuno-suppression, in particular as to whetherthe presence of irAEs may augment orhinder the anti-tumour response. One sen-tinel single centre study of 298 patientsprovides a glimpse of the magnitude andgravity of irAEs.17 In this study of low-dose anti-CTLA4 therapy for advancedmelanoma, irAEs were observed in 85% ofpatients, with 103 patients requiring glu-cocorticoids and 29 patients who did notrespond to initial steroid treatment requir-ing a second biological agent (generally ananti-tumour necrosis factor, most com-monly for colitis).17

The future of checkpoint therapy isbright; there is an expanding horizon ofmolecular targets—some of which arealready are in development—includingPD-1 ligands, TIM-3, LAG-3 and othersused singly and in combination.18 Thisalso raises the spectre of new and possiblyunrecognised forms of irAEs. The rheu-matology community is far closer to thebeginning of this entire story than someother specialties and this report shouldserve as a wakeup call for clinicians to

familiarise themselves with these agentsand the evolving literature and be poisedto identify and manage such complica-tions in concert with our oncologycolleagues.

Contributors Both authors collaborated in allelements of the writing.

Competing interests None declared.

Provenance and peer review Commissioned;externally peer reviewed.

To cite Calabrese L, Velcheti V. Ann Rheum Dis2017;76:1–3.

Received 21 June 2016Revised 9 August 2016Accepted 10 August 2016Published Online First 26 August 2016

▸ http://dx.doi.org/10.1136/annrheumdis-2016-209595

Ann Rheum Dis 2017;76:1–3.doi:10.1136/annrheumdis-2016-209782

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