A Review of Immune Checkpoint Blockade for the General Surgeon

Abstract

The immune system is a complex and interconnected system that has evolved to protect its host from foreign pathogens. CD8⁺ T cells are a type of immune cell that can be directly lethal to tumor cells. However, their tumor killing capabilities can be inhibited by checkpoint molecules. During the last decade, the development of medications that block these checkpoint molecules has revolutionized treatment for some cancer types and indications for use continue to grow. As usage of immunotherapy increases, toxicities and adverse unique to immunotherapy are becoming more prevalent. Here, we review the commonly targeted inhibitory molecules along with their food and drug administration (FDA) approved indications in various cancer therapeutic regimens, immunotherapy-related toxicities, and how this may impact surgical planning.

Introduction to the Immune System

The immune system is a complex and interconnected system that has evolved to protect its host from foreign pathogens. The immune system has two major components: innate immunity and adaptive immunity. The innate immune system, comprised of neutrophils, macrophages, natural killer cells and the complement system, acts immediately upon recognizing a foreign antigen to tag and phagocytose or lyse its targets. The late or adaptive immune system is comprised of B cells and T cells and is marked by its specificity as well as its ability to form memory cells which can recognize antigens upon repeated exposures. This response is dependent upon B and T cells recognizing antigen, which are which are peptides derived from foreign pathogens (or in the case of autoimmunity, the self). B cells have the capacity to produce pathogen- or tumor-specific antibodies after activation, which can then tag unwanted cells for clearance through antibody-dependent cellular cytotoxicity, antibody-dependent phagocytosis, or the complement system. In contrast, T cells use effector functions to kill pathogens directly. Together, the innate and adaptive immune systems work in a coordinated effort to help the host remain disease free.^1–3

The immune system is not only designed to kill foreign pathogens but also plays a critical role in the surveillance, detection and elimination of cancer cells.⁴ CD8⁺ T cells, also known as cytotoxic T lymphocytes, are capable of killing tumor cells and their presence in the tumor microenvironment is associated with improved prognosis in cancer.^5,6 In order to effective at tumor cell killing, CD8⁺ T cells require two important signals. First, they must recognize antigens presented by major histocompatibility complexes (MHC)⁷. The second signal can either stimulate or suppress T cell activation. Therefore, this second signal molecule serves as a either a co-stimulatory signal or a “checkpoint” for CD8⁺ T cell effector functions. Tumor cells can display inhibitory checkpoint molecules which suppress CD8⁺ T cells responses and allow the tumor to evade the immune system.⁸ In the last decade, drugs which block this second inhibitory signal, called immune checkpoint blockade, release the brakes that these inhibitory molecules have placed on CD8⁺ T cells. This then unleashes the power of CD8⁺ T cells to kill tumor cells.

The purpose of this review is to summarize our current understating of immune checkpoint blockade (ICB). We will define checkpoint molecules and their associated drugs. We will also describe the indications for checkpoint blockade in the non-metastatic setting. Lastly, we will detail the potential complications of immune checkpoint blockade and their implications for surgeons.

Checkpoint Molecules

As mentioned above, CD8⁺ T cells can either be activated or suppressed by a second signal after they engage with MHC-bound antigen. The balance created by the second signal is important to preserve self-tolerance and prevent autoimmunity while still promoting host defense. Co-stimulatory and co-inhibitory ligands and their receptors are present on T cells as well as the antigen presenting cells (APCs) that present foreign antigens. The main co-stimulatory molecules for T cells are CD28, OX40, GITR, and 4–1BB.⁹ Co-inhibitory molecules are often upregulated on T cells through a negative feedback loop. These molecules are also present on immune cells that regulate T cell activity, APCs, and normal nucleated cells to prevent autoimmunity. We discuss four different immune checkpoint molecules along with names of the corresponding Food and Drug Administration (FDA) approved monoclonal antibody therapies. Figure 1. Table 1.

Figure 1.

Checkpoint Inhibitory and Stimulatory Molecules

Immune checkpoint receptors and their ligands. Immune checkpoint molecules bound to their respective ligands produce a positive or negative signal to CD8⁺ T cells.

MHC: major histocompatibility complex

Figure created with Biorender.com

Table 1.

List of FDA approved checkpoint blockade drugs

Target	Agent
Cytotoxic T lymphocyte antigen-4 (CTLA-4)	Ipilimumab
Programmed Death-1 (PD-1)	Pembrolizumab
	Nivolumab
	Cemiplimab
	Dostarlimab
Programmed death-ligand 1/2 (PD-L1/L2)	Atezolizumab
	Avelumab
	Durvalumab
Lymphocyte Activation Gene-3 (Lag-3)	Relatlimab

Cytotoxic T lymphocyte antigen-4 (CTLA-4)

CTLA-4 is an intracellular protein which is a potent inhibitor of T cell responses that translocates to the cell surface after T cell activation. It is homologous to the co-stimulatory molecule CD28 and binds to the same ligand (CD80) with a higher affinity. By outcompeting CD28, it prevents proliferation and activation of T cells. In the setting of cancer, CTLA-4 is often found on regulatory T cells that inhibit CD8⁺ T cells. Ipilimumab is the only ICB approved by the FDA in 2011 that targets CTLA-4.¹⁰

Programmed Death-1 (PD-1)

PD-1 is a transmembrane protein that is upregulated with repetitive stimulation of T cells. PD-1 has two ligands, programmed death-ligand 1 (PD-L1) and programmed death-ligand 2 (PD-L2), that when engaged, inhibit T cells. Tumor cells upregulate PD-L1 and PD-L2 to diminish immune cell killing. In addition to inhibition of intracellular T cell signaling, PD-1 engagement depresses CD8⁺ T cell metabolism and decreases transcription of pro-survival factors.¹¹ Nivolumab and pembrolizumab are checkpoint blockers that target the PD-1 molecule and were both FDA approved in 2014. In 2018 and 2021, cemiplimab and dostarlimab were also approved, respectively.^12,13.

Programmed death-ligand 1/2 (PD-L1/L2)

PD-L1/L2 are cell surface proteins that are expressed on tumor cells and even some immune cells in the tumor microenvironment. Its receptor is PD-1 and blockade of PD-L1/L2 results in enhanced anti-tumor immunity, similar to PD-1 blockade. Expression of PD-L1/2 in the tumor microenvironment is upregulated by interferon-γ, which is an effector molecule of CD8⁺ T cells. Atezolizumab, avelumab, and durvalumab are all FDA approved PD-L1 inhibitors.^12,14

Lymphocyte Activation Gene-3 (Lag-3)

Lag-3 is a transmembrane receptor expressed on CD8⁺ T cells and is further upregulated by T cell activation. Its exact ligand is unknown. Upon engagement, Lag-3 negatively regulates CD4⁺ and CD8⁺ T cell activation, proliferation, and function. Relatlimab is the only FDA approved Lag-3 inhibitor.¹⁵

FDA Approved Indications for ICB in Non-Metastatic Cancer

Advanced disease

Mismatch Repair (MMR)/Microsatellite Instability (MSI)

Mismatched nucleotides in DNA occur as a result of chemical and physical insults as well as polymerase integration errors.¹⁶ Mismatch repair (MMR) is one of the DNA repair pathways that recognizes and replaces these mismatched nucleotides. Loss of function in MMR genes, such as MLH-1, MSH-2, MSH-6 and PMS-2 lead to MMR deficiency associated with microsatellite instability (MSI). MSI is associated with an increased risk of numerous cancers given the correlative increase in mutations, which is particularly well studied in colorectal cancers.¹⁷ MMR/MSI and the resultant tumor mutational burden creates a tumor microenvironment which is highly infiltrated with immune cells that facilitates checkpoint blockade efficacy. ICB has been approved for dMMR (MMR deficient) or MSI-H (MSI-high) solid cancers including colorectal^18,19, pancreatic, endometrial²⁰, and prostate cancer.²¹ Most recently, dMMR/MSI-H was FDA approved as a pan-cancer biomarker for pembrolizumab use given the tissue agnostic association between dMMR and response to checkpoint blockade. ²²

Lynch syndrome, or hereditary non-polyposis colorectal cancer, is a hereditary syndrome marked by pathogenic mutations in one of the four MMR genes and is the most common hereditary colon cancer syndrome. It is also associated with endometrial cancer, ovarian cancer, urothelial cancer, small bowel cancer, gastric cancer, and brain tumors. In a study looking at 27 tumor types, 3.8% were MSI-H.²³ About 14% of all colon cancers are MSI-H and the majority occur as a result of sporadic inactivation of the MMR pathway. About 2–3% of all colorectal and endometrial cancer causes are associated with germline mutations in a MMR gene and cancer-specific inactivation of the second allele. Interestingly, in patients with dMMR/MSI-H colorectal or non-colorectal cancer associated with Lynch Syndrome, response rates to ICB appear to be similar to those with sporadic dMMR/MSI-H cancers.^{24 25} Most recently, a clinical trial of single-agent anti-PD-1 monoclonal antibody (dostarlimab) was given neoadjuvantly to Stage II or III patients with MMRd colorectal cancer and 100% of the 12 patients enrolled had a complete clinical response and none had required surgery or chemoradiotherapy at follow-up.²⁶ Each of the initial 14 patients enrolled had confirmed MSI and high tumor mutational burden. While none had a family history of Lynch syndrome, 57% were found to have pathogenic mutations in genes associated with Lynch syndrome.

Skin Cancer

Melanoma

In 2011, Ipilimumab was the first ICB to receive approval for advanced or metastatic melanoma patients.²⁷ The approval of ipilimumab, based on the MDX010–20 trial, led to the approval of several other ICB drugs for use in patients with unresectable or stage III melanoma.²⁸ For example, in 2014, anti-PD-1 inhibitors, nivolumab or pembrolizumab alone, were found to extend survival.²⁷ Further studies have shown that combination therapy of nivolumab and ipilimumab improved progression free and overall survival compared to monotherapy with either agent.²⁹ Combination relatlimab (LAG-3 blocking antibody) and nivolumab are also approved use based on the combinations improved outcomes compared to nivolumab alone. ³⁰

Non-melanoma skin cancer

Basal cell and squamous cell carcinoma are the two most common types of non-melanoma skin cancer, and have indications for treatment with the PD-1 inhibitor, cemiplimab.³¹ In 2018, cemiplimab was approved in squamous cell carcinoma for patients that were unlikely to receive curable resection.³² In 2021, basal cell carcinoma patients who are intolerant of hedgehog inhibitors were also approved for cemiplimab monotherapy.³³ Finally, based on results from the Keynote-017, pembrolizumab can be used as first line treatment for recurrent locally advanced tumors in patients with Merkel cell carcinoma.³⁴

Head and Neck Cancer

Currently, immunotherapy is approved for use in recurrent unresectable squamous cell carcinoma of the head and neck. The first approval came in 2016 for patients refractory to platinum-based chemotherapy.^35,36 In 2019, pembrolizumab plus platinum and fluorouracil or pembrolizumab alone (if tumors express PD-L1) was approved as frontline therapy³⁷.

Lung Cancer

Small Cell Lung Cancer (SCLC)

SCLC is divided into limited disease (one side of the chest) and extensive disease. Traditionally, extensive-stage small cell lung cancer (ES-SCLC) was treated with platinum plus etoposide.³⁸ In 2018, atezolizumab plus carboplatin and etoposide was approved for patients with ES-SCLC as first line treatment after the Impower133 trial showed longer progression free and overall survival compared to chemotherapy alone.³⁸ Shortly after, in 2020, the PD-L1 inhibitor durvalumab plus chemotherapy was approved as first line treatment.³⁹

Non-Small Cell Lung Cancer (NSCLC)

ICB can be used in unresectable NSCLC, in addition to early-stage disease (discussed below). Durvalumab was approved in 2018 for patients with stage III NSCLC following chemoradiation. In comparison with placebo, durvalumab led to improvements in 18-month PFS (27.0% [95% CI, 19.9 to 34.5], 44.2% [95% CI, 37.7 to 50.5]).⁴⁰ In patients whose tumors have PD-L1 expression, cemiplimab plus platinum-based chemotherapy was approved in 2021 based on improved outcomes with the addition of cemiplimab to chemotherapy.⁴¹

Excretory System Cancer

Urothelial Carcinoma

Urothelial carcinoma is the most common malignancy in the urinary tract and approximately 5% of patients develop invasive disease that cannot be managed with surgical resection.⁴² These patients require cisplatin based chemotherapy, however there are patients who are not eligible for this regimen. In 2017, both pembrolizumab and atezolizumab were approved for the treatment of patients with locally advanced urothelial carcinoma who are ineligible for platinum-based therapy.⁴³ For patients who do undergo platinum-based chemotherapy, avelumab given as maintenance after chemotherapy showed improved overall survival (71.3% [95% CI, 66.0 to 76.0]) compared to placebo (58.4% [95% CI, 52.7 to 63.7], leading to FDA approval for this indication. Lastly, nivolumab is approved for urothelial carcinoma after radical surgical resection for high-risk disease regardless of neoadjuvant treatment regimen.⁴⁴

Renal Cell Carcinoma

Renal cell carcinoma (RCC) is generally characterized as chemotherapy resistant, however both anti-angiogenic agents and ICB have proven effective in RCC. ICB potentiates the effects of vascular endothelial growth factor (VEGF) inhibitors, which are standard of care first line therapy for advanced RCC.⁴⁵ Combination therapy of the PD-1 inhibitor, pembrolizumab, or PD-L1 inhibitor, avelumab, plus the VEGF inhibitor axitinib has been approved for advanced RCC.^46,47 The CLEAR trial randomized patients with advanced RCC to the VEGF inhibitor penvatinib plus pembrolizumab, lenvatinib plus everolimus or sunitnib (VEGF inhibitor) alone and showed that pembrolizumab plus lenvatinib improved PFS (median, 23.9 vs. 9.2 months) when compared to sunitinib alone.⁴⁸ Additional ICB combinations including those with the CTLA-4 inhibitor, ipilimumab, for advanced RCC have also been approved.^49,50 Finally, in patients with high risk disease who have undergone surgical resection, adjuvant pembrolizumab improved disease-free survival compared to placebo alone. (CHOUEIRI)

Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancer. The pathogenesis of HCC is often related to chronic inflammation due to infection (Hepatitis) or steatohepatitis.⁵¹ This inflammation can also be associated with an immunogenic environment, making ICB a potential therapy for this cancer which can be difficult to treat. For patients previously treated with sorafenib, the addition of pembrolizumab as a second-line therapy improved outcomes.⁵² In untreated patients with unresectable disease, the combination of atezolizumab plus bevacizumab led to an increase in overall survival at 12 months (67.2% [95% CI, 61.3 to 73.1]) compared with sorafenib alone (54.6% [95% CI, 45.2 to 64.0]).⁵³

Early-stage disease / Neoadjuvant Use

As with many new drugs, the first studies of ICB have been in the unresectable and metastatic stages. More recently, ICB has been tested in early-stage disease with benefits shown in breast, lung, and skin cancers. ICB has approval for use in the neoadjuvant setting in both triple negative breast cancer and non-small cell lung cancer. FDA approval for ICB plus chemotherapy for neoadjuvant use in triple negative breast cancer (TNBC) patients with high-risk stage II and III disease came on the heels of the Keynote 522 trial results which showed improved pathologic complete response (pCR) and event free survival (EFS) (by 7 months) with ICB plus chemotherapy compared to chemotherapy alone.⁵⁴ The PD-1 inhibitor, nivolumab, is approved for use in early stage non-small-cell lung cancer (NSCLC) based on a study showing improved pCR and EFS with the addition of nivolumab to chemotherapy.⁵⁵ In the adjuvant setting, atezolizumab is approved for stage 1B – IIIA non-small-cell lung cancer following standard chemotherapy.⁵⁶ Lastly, pembrolizumab has also been approved in the adjuvant setting for 1 year following surgical resection in patients with stage IIB or IIC melanoma.⁵⁷

Checkpoint Blockade Toxicity

ICB has a unique side-effect profile related to its mechanism of action. The activation of T-cells which occurs with ICB treatment can damage off-target tissues. Toxicities from ICB are called immune-related adverse events (irAEs). The overall rate of any toxicity from immunotherapy ranges from 70% to 80% for anti-CTLA-4 and anti-PD-1/PD-L1 therapies (and even higher with dual therapy).^{58 59,60} Up to almost half of patients in published studies using ICB discontinued treatment at some point due to irAEs. ^61,62 The incidence of fatal irAEs is between 0.3% and 1.3%,⁶³ which is slightly lower than most conventional chemotherapy and targeted therapy regimens. It is imperative that surgeons be aware of potential complications from immunotherapy. IrAEs can present within weeks after starting therapy (most commonly) but can present months or years later, even after therapy has been stopped.^58,64 As ICB use in the neoadjuvant setting becomes more common, surgeons will become increasingly responsible for recognizing toxicities. As the prevalence of ICB increases, early identification is a key to successful management.

Mechanism of ICB toxicity

The CTLA-4 and PD-1/PD-L1 checkpoint molecules restrain T-cell function at different stages. Blockade of CTLA-4 works on T-cells proximally in the activation pathway resulting in cessation of proliferation and activation of T-cells.¹⁰ PD-1 restrains T-cells more distally and in peripheral tissues when it is upregulated due to inflammation, as is the case in the tumor microenvironment.^12,64 While toxicity in blockade of either pathway is the result of auto-reactive T-cells, antibodies, or cytokines which are released by the activated T-cells, the differing sites of activity of these checkpoint molecules result in different patterns of toxicity. Anti-CTLA-4 toxicity is often more severe and more likely to present as colitis or hypophysitis compared to anti-PD1/anti-PD-L1 toxicity, which more commonly presents as pneumonitis and thyroiditis.⁶⁴ Fatal toxicity also tends to differ depending upon the agent used. Colitis is the most frequent cause of death in patients treated with anti-CTLA-4. Pneumonitis followed by hepatitis and neurotoxic events are the most common cause of anti-PD-1/anti-PD-L1 related death.⁶⁵

Common ICB toxicities

Not surprisingly, given the ubiquity of T-cells in the human body, nearly all organ systems can be adversely impacted by ICB. (Table 2) Unlike patients treated with conventional cytotoxic chemotherapy, hematologic related events are much less common in patients treated with ICB. Autoimmune hemolytic anemia, autoimmune thrombocytopenia, acquired hemophilia A, and thrombotic thrombocytopenic purpura have all been reported as rare events.⁶⁵ Cutaneous toxicities on the other hand, are extremely common and up to half of all patients treated with ICB experience a cutaneous irAE. The most common skin irAEs are rash, pruritis and vitiligo.⁶⁶ Rarer cutaneous irAE include ulcerative or bullous dermatitis, urticaria, xerosis, hyperhidrosis, changes in hair, and lupus-like reactions.^67–69 Patients with a personal or family history of psoriasis may also experience relapse, worsening or emergence of psoriatic skin changes.⁷⁰

Table 2.

Potential immune-related adverse events (irAEs) related to immune checkpoint blockade

Organ System	irAEs Reported in Literature
Neurologic	Encephalitis, myasthenia gravis or myositis and Guillain-Barre or Guillain-Barre-like syndrome, cerebellar ataxia, retinopathy, peripheral neuropathies, disorders of the neuromuscular junction, asymmetric mononeuritis multiplex
Ocular	Uveitis, dry eyes
Endocrine	Hypophysitis, primary adrenal insufficiency, hypothyroidism, hypoparathyroidism, type I diabetes
Cardiac	Cardiac myositis
Pulmonary	Pneumonitis, cryptogenic organizing pneumonia (COP), sarcoid-like lung disease, hypersensitivity pneumonitis, interstitial pneumonia, even acute respiratory distress syndrome
Gastrointestinal	Diarrhea, colitis, hepatitis, acute liver failure
Renal	Acute interstitial nephritis, lupus nephritis
Skin	Rash, pruritis and vitiligo, ulcerative or bullous dermatitis, urticaria, xerosis, hyperhidrosis, changes in hair, lupus-like reactions, psoriasis relapse
Rheumatologic	Arthralgia, myalgia, inflammatory arthritis, vasculitis, myositis
Hematologic	Autoimmune hemolytic anemia, autoimmune thrombocytopenia, acquired hemophilia A, thrombotic thrombocytopenic purpura

Endocrinopathies are relatively common irAEs and are different than adverse events typically seen with traditional cytotoxic chemotherapy. Hypophysitis, or inflammation of the pituitary gland, occurs in up to 12–13% of patients treated with ICB.⁷¹ Hypophysitis may have a vague presentation of headache and fatigue and therefore it is imperative clinicians are aware of this irAE which occurs more frequently in elderly, male patients, and those treated with anti-CTLA-4 or dual ICB. Hypophysitis results in multiple hormone deficiencies, most commonly central hypothyroidism and adrenal insufficiency.⁷¹ Patients may also suffer from a variety of other endocrinopathies including secondary hypothyroidism (4–19.5%), primary adrenal insufficiency (approximately 1%), hypoparathyroidism, and type I diabetes (<1%) which so far has only been reported in those treated with anti-PD-1/PDL-1 therapy.⁷¹

Cardiopulmonary toxicity has the potential to be life-threatening. ICB-associated myocarditis is a severe complication that occurs in 1.4% of patients and has a high risk of death. It is the most fatal irAE and is the cause of almost 40% of all deaths related to ICB). ⁷² Cardiac toxicity more commonly occurs in patients treated with dual ICB. ICB-associated myocarditis has a range of presentations including asymptomatic myocardial infarction, chest pain, shortness of breath, or acute circulatory collapse.⁶⁵ Immune-related pneumonitis is also life-threatening complication that occurs in 1–5% of patients treated with ICB.⁷³ Pulmonary irAEs are more common in patients being treated for NSCLC than other diseases and present most commonly as cryptogenic organizing pneumonia (COP), sarcoid-like lung disease, hypersensitivity pneumonitis, interstitial pneumonia or even acute respiratory distress syndrome.⁶⁵

Toxicity impacting the lower gastrointestinal track occurs in 10–20% of patients and ranges from mild diarrhea to colitis that can be severe, mimicking inflammatory bowel disease.⁷⁴ Endoscopy and biopsy are often required for diagnosis.⁷⁵ Hepatitis may also occur in 5–10% of patients treated with ICB and ranges from mild elevations in liver function tests to hyperbilirubinemia and coagulopathy and rarely, acute liver failure ⁷⁶.

Other, less common irAEs involve the neurologic, ocular, rheumatologic and renal systems. Neurologic irAEs have a wide range of manifestations including encephalitis, myasthenia gravis or myositis and Guillain-Barre or Guillain-Barre-like syndromes as well as other rare complications such as cerebellar ataxia, retinopathy, peripheral neuropathies, disorders of the neuromuscular junction, and asymmetric mononeuritis multiplex.⁶⁵ Uveitis and dry eyes are the most common reported irAEs in those treated with ICB, based on a review of eleven trials.⁷⁷ In a systematic review of the literature, Capelli and colleagues identified arthralgia and myalgias as common irAEs, occurring in up to 45% of patients.⁷⁸ Case reports detail incidences of inflammatory arthritis, vasculitis, lupus nephritis, and myositis though the connection to ICB is less clear. Acute interstitial nephritis is the most common irAE to impact the kidney and is likely caused by loss of self-tolerance.⁶⁵

Timeline of ICB toxicity

IrAEs are generally graded based on the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE). Grades 1 and 2 are considered mild and grades 3 and 4 are serious. The majority of serious (grade 3 or 4) irAEs occur within 8–12 weeks from starting treatment. Dermatologic manifestations typically have the earliest onset, followed by hepatotoxicity, which tends to occur earlier than 8–12 weeks. Rheumatologic and renal irAEs often present later from the initiation of treatment.⁶⁵ Fatal toxicities have a rapid onset, particularly when compared to those caused by other drugs used in the treatment of cancer, with a median time to onset of fatal toxic event at 14.5 days (for dual ICB therapy) and 40 days in single agent ICB therapy.⁷⁹ It is important to note that late-onset and long-lasting irAEs are likely underreported and relatively common⁸⁰. This point is particularly important for the practicing surgeon, who may be the first to diagnose an irAE in patient treated with neoadjuvant ICB.

Monitoring and Treatment of ICB toxicity

Consensus guidelines have been developed to help screen for and treat irAEs.⁸¹ Prior to initiating ICB, consideration should be given to obtaining a complete history and physical exam with focus on autoimmune diseases and bowel habits, as well as baseline oxygen saturation and dermatologic and mucosal exam. Baseline bloodwork should include CBC, CMP, TSH, HbA1c, Free T4, total CK, fasting lipids, hepatitis screen, ECG troponin at baseline and weekly for 6 weeks.⁸¹ Patients should be educated about irAEs and the treatment team will need to be familiar with irAEs as rapid identification can be crucial in preventing mortality from potentially fatal irAEs.

The main pillars of treatment for irAEs are withdrawal of ICB and treatment with steroids and other immunosuppressive medications.^62,82 For patients with grade 1 irAEs, steroids are usually not indicated, and treatment can be continued. For those with grade 2 irAEs, oral and potentially intravenous steroids may be used. Therapy should be held while steroids are given and until toxicity reaches grade 1 level. Patients with grade 3 or 4 toxicities should be treated with intravenous steroids and immunotherapy should be held. For grade 3 toxicities that do not resolve in 4–6 weeks and any grade 4 toxicity, immunotherapy should be permanently discontinued. Patients with severe irAEs who fail to improve on steroids may benefit from the addition of an added immunosuppressive agent, such as infliximab. Patients on steroids should be placed on proton pump inhibitors and for those on steroids > 3 weeks, prophylaxis against PCP should be given. ⁸¹. New drugs are also in development, such as vedolizumab, an integrin receptor antagonist that acts specifically on the gut.

Surgeons should also be aware that immune-related colitis can be quite severe and may require endoscopy and biopsy for diagnosis.⁷⁵ Surgical intervention is only necessary in cases of perforation, abscesses that cannot be drained percutaneously, toxic megacolon, intractable bleeding, or treatment refractory disease.⁸³

ICB Toxicity and its relationship to response to therapy

The occurrence of an irAE is evidence that the patient’s immune system has been activated. This has led some to postulate that those with irAEs may have better immune activation and therefore a better treatment response. Some studies have demonstrated an association between irAEs and anti-tumor response as well as an increase in survival in those with more irAEs.^84–86 However, other studies have shown that specific irAEs may be associated with worse outcomes. The implication that irAEs are a sign of a productive immune response against tumor remains controversial. This is due to concerns about statistical analyses used in studies that support this and the challenges in diagnosing irAEs and also attributing clinical findings to ICB.⁸⁷

Complications and use of immunotherapy in the neoadjuvant setting

Immunotherapy continues to gain approval for use in the neoadjuvant setting and irAEs can happen in the perioperative setting. The onus is therefore on the surgeon, to suspect and diagnose irAEs, which as described above, can be both life-threatening and at the same time, have a vague presentation.

Data is limited on optimal timing of surgery for patients treated with neoadjuvant ICB. Studies from patients with metastatic cancer who subsequently underwent surgery after treatment in the neoadjuvant setting show no specific complications related to the timing of ICB^88–94 and that patients undergo surgery as soon as 2 weeks post-treatment. Those who experience more severe irAE are more likely to experience delays. Many advocate for pre-operative work-up to evaluate for irAEs, particularly adrenal insufficiency, in those who have completed neoadjuvant immunotherapy.⁸³

The future of immune checkpoint blockade

While the approval of ICB has been a major landmark for some diseases, work is ongoing to discover combination therapies to improve response rates, to make certain tumors immunologically “hot” so they will respond to ICB, and to identify biomarkers to predict what patients will respond to ICB. In addition to PD-1/PD-L1, checkpoint molecules adenosine A2AR, Lag-3, TIM3 are under investigation as potential co-inhibitors. Several other molecules, such as GITR, 4–1BB, OX40, CD27 are being evaluated as co-stimulatory targets to add to ICB.⁹⁵ Other studies have focused on making immunologically cold tumors hot by enhancing T-cell priming and activation (oncolytic viruses, chemotherapy, radiotherapy, thermal ablation, epigenetic modification inhibitors, photothermal and photodynamic therapy), expanding T-cells (adoptive cellular therapy, vaccines) and improving T-cell trafficking to and infiltration into the tumor microenvironment (antiangiogenic therapy, TGFb inhibitor, CXCR4 inhibitor, epigenetic modification inhibitor, oncogenic pathway inhibitors).⁹⁶ Finally, in addition to the known biomarkers PD-L1, tumor mutational burden, microsatellite instability, and mismatch repair deficiency, efforts are underway to uncover additional biomarkers of response including circulating and microbiome biomarkers.⁹⁷

As these advances move to the clinics, the care of cancer patients will become even more nuanced. Surgeons will need to remain aware of how new therapies influence the ordering of treatment and take shared ownership over recognizing and addressing irAEs.