key: cord-0946078-sfvr269q
authors: Johnson, Douglas B.; Jakubovic, Baruch D.; Sibaud, Vincent; Sise, Meghan E.
title: Balancing cancer immunotherapy efficacy and toxicity
date: 2020-06-26
journal: J Allergy Clin Immunol Pract
DOI: 10.1016/j.jaip.2020.06.028
sha: 80ae1771987eb6c8ff6513f219214e9c00f761c2
doc_id: 946078
cord_uid: sfvr269q

Abstract Anti-programmed death-1/ligand-1 (PD-1/PD-L1) directed therapies are transforming cancer care, with durable anti-tumor responses observed in multiple cancer types. Toxicities arising from therapy are autoimmune in nature and may affect essentially any organ system. The immunologic basis of such toxities is complex, with contributions from T cell activation and autoantibody generation. Though less recognized, hypersensitivity reactions are also possible. Although most toxicities resolve with systemic corticosteroids, some require second-line immunosuppression. Further, the safety of drug rechallenge is not well-characterized, with variable rates of toxicity flares arising with re-exposure. Herein, we review toxicities of immune checkpoint inhibitor therapies, particularly focusing on issues that allergists/immunologists may clinically encounter, including interstitial nephritis, skin toxicity, and risks associated with immunotherapy rechallenge.

A 67 year old man with metastatic non-small cell lung cancer, hypertension, and 35 gastroesophageal reflux, presents to your clinic for evaluation of possible drug hypersensitvity. 36

He has been receiving pembrolizumab 2mg/kg IV every 3 weeks for the past 15 months and 37 has had a partial response to therapy, with decreased tumor burden by approximately 50%. For 38 the first year on therapy, his only complaint had been an intermittent grade 1 maculopapular 39 eruption on his arms and trunk (less than 10% of body surface area affected), which had been 40 managed with topical triamcinolone and occasional cetirizine 10mg daily. Approximately 1 41 month prior to presentation, he developed worsening of his kidney function on routine laboratory 42 evaluation, with increased creatinine to a peak of 3.5 mg/dl (baseline 1.1 mg/dl). His other long-43 standing medications included omeprazole and hydrochlorothiazide. He reported no decreased 44 oral intake, and did not have recent exposure to intravenous contrast nor any over-the-counter 45 medications. No other symptoms were detected on review of systems. His blood counts were 46 normal, including a normal leukocyte differential. Urinalysis showed trace proteinuria, no 47 erythrocytes, and 3-5 leukocytes without cellular casts noted on urine microscopy. Renal 48 ultrasound was unremarkable. Pembrolizumab was withheld, and the patient was treated with 49 prednisone 1mg/kg with normalization of his creatinine over the next week. Prednisone was 50 tapered over the subsequent 4 weeks and he is now taking prednisone 10mg daily with plans to 51 discontinue in 3 days. The patient asks whether he can receive more pembrolizumab. 52 53 Overview: Immune checkpoint inhibitors 54

Immune checkpoint inhibitors (ICI) are monoclonal antibodies that remove key negative 55 regulators of T cell function. These agents are approved in 17 different cancer types, and have 56 radically transformed oncology treatment paradigms.(1) Approved agents include 57 pembrolizumab, nivolumab, and cemiplimab, which target the programmed cell death-1 receptor 58

(PD-1); atezolizumab, avelumab, and durvalumab, which target the PD-1 ligand (PD-L1); and 59 drugs (PD-1 binds PD-L1 and PD-L2; whereas PD-L1 binds PD-1 and B7-1), inhibition of either 85 PD-1 or PD-L1 produces largely similar clinical outcomes. 86 87 Overview: ICI toxicities 88

The power of blocking these key immune regulators and unleashing anti-tumor T-cell 89 responses is most evident in the improved survival even in cancers for which standard therapies 90 were associated with abysmal outcomes (i.e., Stage 4 melanoma). However, the drawback of 91 this strategy is that widespread T cell disinhibition may generate autoreactive T cells capable of 92 targeting self antigens and host tissues. These aberrant responses produce autoimmune-like 93 adverse events that may involve essentially any organ system, although most often involve the 94 skin, thyroid, colon, and lungs.(8) Toxicities may occur any time while on therapy (even up to 6 95 months after discontinuing treatment), but peak between 1 and 12 weeks after starting. Hence, 96 drug-induced immune-related advsere events(iRAEs) should be considered in the differential 97 diagnosis in all patients exposed to ICIs. Severe immune-related toxicities occur in 98 approximately 20% of patients on anti-PD-1 (likely slightly lower rates with anti-PD-L1), and 40-99 50% of patients treated with combined PD-1/CTLA-4 blockade.(9) Similarly, mild irAEs occur in 100 nearly all patients treated with combination therapy compared with 60-70% of patients on anti-101 PD-1/PD-L1 monotherapy. 102

Technical classification of these events is based on the Clinical Trial Criteria for Adverse 103 Events (CTCAE), an imperfect tool designed to standardize classifications of adverse events on 104 clinical trials.(10) For the purposes of this review, they may be categorized by severity (mild, 105 moderate, severe) and by response to treatment (responsive vs. refractory). Mild toxicities 106 (CTCAE grade 1), are managed with symptomatic management (e.g. moderate-to high-potency 107 topical corticosteroids for pruritic rash) and continuation of ICI, while treatment may be held for moderate events (CTCAE grade 2). For persistent moderate, severe, or life threatening events 109 (grades 2-4), patients should hold ICI, receive prednisone 1-2mg/kg or equivalent, and 110 supportive management. The persistent pharmacokinetic and pharmacodynamic properties 111 (lasting weeks to months) of ICI requires that severe events be treated with steroids and 112 potentially other immunomodulators rather than simply drug cessation alone. Steroid refractory 113 events may be treated by disease specific immunosuppressants (e.g., infliximab for colitis, 114 mycophenolate mofetil for hepatitis). Although typically manageable with standard treatment 115 algorithms, some toxicities become chronic and occasionally even fatal (in 1.2% of patients 116 treated with combination PD-1/CTLA-4 blockade).(11) In aggregate, steroid-refractory toxicities 117 (defined as those needing steroid re-escalation, second-line immunosuppression, or causing 118 death) occurred in 23% of patients receiving combination therapy and only 3% of those on anti-119 PD-1 monotherapy in one series.(12) Of note, as very little high-level evidence exists for 120 management of ICI-toxicities, most recommendations are based on expert opinion, 121 retrospective series, and anecdotal evidence rather than randomized prospective clinical 122 trials. (13, 14) 123 Monitoring for these irAEs is a critical component of management. Most providers obtain 124 complete blood count and complete metabolic profile at each cycle to monitor bone marrow, 125 kidney, and liver function. Thyroid function tests should be obtained at least every other 126 treatment. We obtain cortisol and troponin measurements to assess for cardiac and adrenal 127 dysfunction specifically for patients on combination PD-1/CTLA-4 blockade. In addition, oxygen 128 saturation may help diagnose pneumonitis. Otherwise, close symptom checks and skin exams 129 at every visit are performed, with particular attention paid to the gastrointestinal, pulmonary, and 130 dermatologic systems. 131

Although the general mechanisms of these events are well known (i.e. removal of 132 immune checkpoints which results in T cell activation), the reasons why certain patients experience organ-specific events or multisystem involvement remain unclear. Proposed 134 mechanisms of toxicity include T-cell targeting of shared antigens common to both tumor and 135 inflamed tissue,(15, 16) pre-existing autoantibodies,(17, 18) and microbial factors (specifically 136 cross-reactive memory T-cell response to a pathogen to which the host has previously been 137 infected) inducing inflammation that is further exacerbated by ICI therapy. (19, 20) Direct T-cell 138 targeting of organ tissue, as well as autoantibody generation may occur with toxicities.(9) As 139 such, these events are distinct from classical drug hypersensitivity. We will briefly review 140 specific toxicities (Table 1) , with more extensive sections on events that may be more relevant 141 to allergists: skin toxicities and interstitial nephritis. Further study into the mechanism of ICI-AIN is needed. 221

It is important to note that a small number of patients develop immune-related 222 glomerular diseases after ICIs with a wide variety of other pathologies found on kidney biopsy, 223 including lupus nephritis, vasculitis, or podocytopathies.(45) As each of these entities may 224 require different treatment strategies, this highlights the importance of kidney biopsy to 225 determine the etiology of AKI in patients on ICI therapy with unexplained AKI or new-onset 226 proteinuria. 227

Fortunately, ICI-AIN commonly responds favorably and quickly to corticosteroids. 228

Guidelines recommend holding ICI and evaluating any patient whose serum creatinine rises 1.5-229 fold above baseline (i.e., ≥ stage 1 AKI), and an empiric course of steroids 0.5-1mg/kg/day is 230 recommended for a patient with stage 2 AKI (≥ 2-fold rise in serum creatinine) when alternative 231 causes are excluded. (13) We also recommend discontinuation of any other medication associated with AIN (such as NSAIDS or proton pump inhibitors). In a multi-center retrospective 233 study, 85% of patients responded to corticosteroids with either partial of rull remission 234 regardless of dose/duration used and less than 10% needed a second-line 235 immunosuppressant.(36) The optimal immunosuppressive treatment for patients who develop 236 immune-mediated glomerular diseases after ICI is unknown. adrenal insufficiency is treated similarly with hormone replacement therapy. Finally, type 1 289 diabetes may rarely (<1% incidence) complicate therapy, and requires insulin supplementation, 290 typically without steroids. (56) The endocrine toxicities all tend to require long-term (likely 291 lifelong) hormone supplementation, as the initial inflammation seems to "burn out" the hormone 292 secreting cells. 293

Among the most ominous and lethal toxicities, myocarditis occurs in up to 1% of treated 295 patients. Myocarditis tends to arise early on therapy (within the first month after starting) and is 296 associated with frequently fulminant and progressive arrhythmias and less commonly 297 cardiomyopathy.(16) Troponin elevation is quite sensitive, and the diagnosis may be confirmed 298 with cardiac MRI or myocardial biopsy, although given the limitations of these tests, patients 299 with arrhythmias and elevated troponin may need empiric treatment.(57) Of interest, this entity 300 frequently presents concurrently with skeletal muscle inflammation and a myasthenia gravis-like 301 syndrome. The fatality rate is up to 50% in one series,(58) which might be mitigated by pulse 302 doses of steroids (e.g. methylprednisolone 1g daily)(59) plus other immunomodulators (e.g. intravenous immunoglobulin, mycophenolate mofetil, or abatacept)(60) although the optimal 304 regimen is not well known. 305

A spectrum of neurologic events may complicate therapy, occurring in up to 5% of 307 patients in aggregate. These arise in 4 general categories: 1) Meningo-encephalitis, 2) 308 Myasthenia gravis, 3) Peripheral neuropathies (including Guillain-Barre syndrome), and 4) 309 

A spectrum of rheumatologic events may occur, most commonly inflammatory arthritis. 319

These patients may have involvement in any joint including knees (more common with 320 combination) or small joints (more common with anti-PD-1).(63) Mild events may be managed 321 with anti-inflammatories; low-or high-dose steroids may also be effective. Steroid-refractory 322 events may respond to methotrexate or tumor necrosis factor (TNF) inhibitors. A subset of 323 patients develop chronic inflammatory symptoms.(64) Other rheumatologic events may also 324 occur, including Sicca Syndrome, scleroderma, and psoriatic arthritis. 325

Essentially any organ system may be affected from ICI toxicities. Other key events to be 327 aware of include uveitis, gastritis, pancreatitis, mucositis, orchitis, and hematologic toxicities 328 (immune thrombocytopenic purpura, hemolytic anemia, hemophilia, aplastic anemia, 329 hemophagocytic lymphangiohistiocytosis). 330

Hypersensitivity reactions including anaphylaxis are increasingly recognized risks of high 332 molecular weight monoclonal antibody therapies, including ICIs.(65) Though treatment-related 333 and immunologically mediated, their mechanisms are distinct from those of iRAEs in that they 334 are generally unrelated to the "on target" effects of the drugs, and on the whole may occur with 335 less frequency. Unlike iRAEs, immediate hypersensitivity reactions may be overcome in the 336 appropriate clinical setting through rapid drug desensitization.(66) It remains unclear whether 337 underlying tendency to hypersensitivity could be unmasked with ICI, although our anecdotal 338 experience does not suggest that this is a common problem. 339

Infusion reactions are extremely rare with most ICI although usually low-grade events 340 (characterized by flushing, rash, fever, rigors, chills, dyspnea, and mild hypotension) may occur 341 in up to 10-20% of patients treated with avelumab.(67) Infusion reactions are likely related to a 342 cytokine release endotype, though a mixed mechanism that also includes mast cell activation is 343 possible.(67) These are generally managed by slowing the infusion, or interrupting and 344 restarting at a slower rate, and premedication with antihistamines.In refractory instances, 345 desensitization could also be considered. 346

Many clinically relevant populations were excluded from ICI clinical trials, including those 348 with dysregulated immune systems (e.g. autoimmune disease, organ transplant), immune 349 suppression (e.g. chronic viral infection, chronic immunosuppressant administration), or difficulty monitoring (e.g. organ dysfunction). While a full summary of these conditions is beyond the 351 scope of this review, use of ICIs in many of these conditions appear to be fairly safe. For 352 example, patients with pre-existing autoimmune disease do appear to have a somewhat 353 increased risk of autoimmune flares, but these are manageable, extremely rarely associated 354 with fatalities, and associated with similar cancer response rates with the general 355 population.(68-71) Similarly, organ dysfunction appears to be safe, although response rates 356 might be slightly lower than in unselected patients. The verdict: Can the patient be rechallenged? 369

Deciding whether to rechallenge a patient with ICI when they have developed an 370 adverse event is a complex one (Table 2) . First, a number of studies have shown that a toxicity 371 with one class of ICI (CTLA-4 vs. PD-1/PD-L1) does not seem to correlate with recurrence with 372 the other class.(69) Although this is only applicable to melanoma, we have also observed that 373 toxicities with combination PD-1/CTLA-4 blockade recur in the minority (~20%) of patients who 374 reinitiate anti-PD-1 alone.(81) Another consideration is whether rechallenge is even needed. A growing body of evidence has shown that many patients who discontinue therapy early for 376 toxicity have equivalent outcomes to those not stopping for toxicity.(82) Factors that would push 377 away from rechallenge include 1) severity of toxicity (with life-threatening events being a near 378 absolute contraindication), 2) steroid-refractory events, 3) longer duration on therapy 379 (suggesting that whatever benefits are to be gained have already been realized), 4) progression 380 of disease, and 5) complete or near complete response. Factors that might suggest rechallenge 381 include 1) very short duration on therapy (e.g. 1-2 doses, suggesting that additional therapy may 382 be needed), 2) recurrence of disease after an extended duration off therapy (e.g. drug is 383 stopped for toxicity during an ongoing response, then 12 months later the disease progresses), 384 and 3) clinically mild toxicity or diagnostic uncertainty. In addition, any other concurrent insults 385 that might predispose to the toxicity (e.g. omeprazole and interstitial nephritis) should be 386 

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