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Gastrointestinal Toxicities of Immunotherapy
Introduction
Novel agents have revolutionized the treatment of cancer, resulting in many benefits for patients. These same agents, however, have been associated with new toxicity profiles compared with traditional chemotherapy. Most of these adverse events have been classified as mild or moderate, but unfortunately, severe and life-threatening complications also occur. This section will focus specifically on immunotherapy and subsequent gastrointestinal toxicity. The various approaches that will be discussed in this section include immune checkpoint inhibitors (ICIs), bispecific antibodies (BABs), chimeric antigen receptor (CAR) T cells, interleukin-2 (IL-2) and interferon-α (IFN-α), which attack cancer cells by activating the immune effector cells and disrupting immune tolerance. Immune therapies can be associated with durable responses; however, they are also associated with multiple toxicities as the activated immune system also attacks normal body cells along with the tumor tissue, resulting in several toxicities. The gastrointestinal system is significantly impacted, resulting in nausea, vomiting, anorexia, diarrhea, colitis, and hepatitis. There have been reports of acute pancreatitis due to ICIs, but clinical pancreatitis is rare and may be considered anecdotal at this time.
Description
IMMUNE CHECKPOINT INHIBITORS
Currently, there are several ICIs that are approved by the US Food and Drug Administration (FDA). Ipilimumab, an anti-cytotoxic T-lymphocyte–associated protein 4 (anti-CTLA-4) antibody, was the first ICI approved to be used in metastatic melanoma. Nivolumab and pembrolizumab, which target programmed cell death protein-1 (PD-1) have been approved for use in melanoma, metastatic non–small-cell lung cancer (NSCLC), head and neck squamous cell cancer, urothelial carcinoma, gastric adenocarcinoma, and mismatch repair deficient solid tumors, as well as for classic Hodgkin’s lymphoma. Nivolumab is also approved for use in hepatocellular carcinoma and in patients with renal cell carcinoma. The combination of nivolumab and ipilimumab has been approved by the FDA for treatment of metastatic melanoma, renal cell carcinoma, and non-small cell lung cancer. Recently, programmed cell death protein-ligand 1 (PD-L1) antibodies have been approved, namely, atezolizumab (urothelial cancer, triple negative breast cancer and NSCLC) durvalumab (urothelial cancer) and avelumab (Merkel cell carcinoma and urothelial cancer) which also block the PD-1 pathway. This field is rapidly evolving, as new agents and combinations continue to be discovered and tested.
BISPECIFIC ENGAGER OF T-CELL ACTIVITY
Blinatumomab is a novel agent for the treatment of B-precursor acute lymphoblastic leukemia (ALL) that has demonstrated encouraging response rates in the setting of minimal residual disease (MRD)-positive (80% complete remission) and relapsed/refractory (R/R) patients. Blinatumomab is a monoclonal antibody which functions as a bispecific T cell engager, or BiTE, that is directed against CD19 on B cells and against CD3 on T cells. It is approved by the FDA for the treatment of R/R, Philadelphia (Ph)-negative and positive B-precursor ALL in adults and children. Due to the above success, the incorporation of blinatumomab in ALL patients in combination with chemotherapy, targeted therapies, or other immunotherapeutic approaches is currently being actively investigated.
CHIMERIC ANTIGEN RECEPTOR T CELLS
In this emerging treatment modality, T cells are isolated from a patient, genetically engineered to express a CAR, and reintroduced into the patient. CAR T cells have demonstrated efficacy primarily in the treatment of relapsed or refractory ALL, chronic lymphocytic leukemia (CLL), and non-Hodgkin’s lymphoma. In August 2017, the FDA approved the first anti-CD19 CAR T cell product, tisagenlecleucel, for the treatment of pediatric and young adult patients with relapsed and/or refractory B-cell precursor ALL. In October 2017, the FDA approved axicabtagene ciloleucel for the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
INTERLEUKIN-2
High-dose IL-2 was the first immunotherapy approved for treatment of metastatic melanoma based on durable responses observed, but recently its use has fallen out of favor due to significant toxicities. IL-2 is also approved for the treatment of renal cell carcinoma.
INTERFERON-α
Patients with resected stage II or III melanoma are at high risk of recurrence. Adjuvant IFN-α has been used in the past to decrease the risk of recurrence of melanoma.
Agents and Mechanism of Action
IMMUNE CHECKPOINT INHIBITORS
Checkpoint inhibitors work by the mechanism of “inhibition of inhibition” and thereafter stimulating the immune system by attenuating tolerance and can result in overwhelming inflammation, tissue damage, and autoimmunity. Checkpoint inhibitors work by inhibition of CTLA-4, PD-1 or PD-2; their ligands that normally limit immune reactions in order to avoid tissue damage, allow tolerance. Ipilimumab inhibits CTLA-4, an inhibitory receptor that is constitutively expressed on CD25(+) CD4(+) T-regulatory cells. CTLA-4 is upregulated on activated T cells and transmits an inhibitory signal to downregulate the immune response, thus acting as an immune checkpoint. As ipilimumab inhibits this signaling, it depletes T-regulatory cells and impairs their function in the blood or tumor microenvironment, thus maintaining T-effector cell activation, and increasing antitumor immunity. PD-1 is an immune checkpoint expressed on the surface of activated T cells. PD-L1 is selectively expressed on many tumors and on cells within the tumor microenvironment in response to inflammatory stimuli, such as interferon-γ. Signaling through the PD-1 pathway results in inhibition of cytokine production and apoptosis of PD-1+ tumor-infiltrating T cells. Along with the activation of the effector T lymphocytes, the ICI leads to the depletion of the regulatory T cells. Depletion of the regulatory T cells removes one of the most important antiinflammatory mechanisms of the immune system because these cells are responsible for the production of inhibitory cytokines, including, transforming growth factor-β, IL-10, and IL-35. By inhibition of this tolerance mechanism, ICIs stimulate cytotoxic T lymphocytes to kill tumor cells, and, as an off-target effect, also result in immune system activation and reactivity against the body’s own organs and tissues. They are known as immune related adverse events (irAEs) and are reported in about 85% of patients after treatment with ipilimumab and up to 70% of patients after blockade of the PD-1 axis. The frequency of severe, life-threatening or even fatal (grade ≥3) events is higher after ipilimumab (10%–40%) compared to nivolumab or pembrolizumab (<5%). , Combination of ICIs results in an increase in the incidence of severe toxicity. The various gastrointestinal (GI) manifestations of ICIs include nausea, vomiting, diarrhea, colitis, and hepatitis.
GI Manifestations With Immune Checkpoint Inhibitors
Anti-CTLA-4.
Gastrointestinal tract irAEs following anti-CTLA-4 inhibitors can range from mild diarrhea to severe colitis, or even death. The most common presentation is diarrhea (27%), followed by colitis. Severe enterocolitis unresponsive to immunosuppressive therapy that may even require a subtotal colectomy, as well as perforation or intractable diarrhea, has been reported in the early trials. These are now rare as the condition is recognized and treated aggressively. The median time of onset of ipilimumab-associated colitis is about 34 days. Some reports, however, note a correlation between adverse events and tumor regression, suggesting that toxicity may serve as evidence of immune activation.
Anti-PD-1.
The number of adverse events with anti-PD-1 therapies has been reported to be less than with anti-CTLA-4. Nivolumab treatment resulted in diarrhea and colitis in 17% of melanoma patients, with grade 3 toxicities in only 1.2% of patients. Pembrolizumab resulted in colitis in 2.8% of patients, and here a positive correlation was noted between the dosage and the adverse events. The median time of onset of irAE was longer for pembrolizumab (18 weeks) than for nivolumab (6 weeks).
Combination Anti-CTLA-4 and Anti-PD-1 Therapy.
The frequency of colitis reported in the literature ranges from 8% to 27%, but the incidence of diarrhea is around 54% in patients treated with anti-CTLA-4 and anti-PD-1 combination therapy. In a meta-analysis of patients treated with ICIs, the relative risk (RR) of all-grade diarrhea and colitis was 1.64 (95% confidence interval [CI], 1.19 to 2.26; P = .002) and 10.35 (95% CI, 5.78 to 18.53; P < .001), the RR of high-grade diarrhea and colitis was reported to be 4.46 (95% CI, 1.46 to 13.57; P = .008) and 15.81 (95% CI, 6.34 to 39.42; P < .001), respectively. RR of upper-GI symptoms (e.g., vomiting) was not significant. Frequency of intestinal perforation has been described at approximately 1%. Compared with lower GI toxicities, the incidence of upper GI toxicities, namely, dysphagia, nausea/vomiting, and epigastric pain, is much less common.
Hepatitis Associated With Immune Checkpoint Inhibitors
Hepatitis is a less frequent complication of ICI therapy. It is characterized by elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST), with or without increased bilirubin. The median onset of transaminase elevation is approximately 6 to 14 weeks after starting ICIs. Hepatitis is generally picked up on routine laboratory evaluation, but some patients may also present with fever or abdominal discomfort. Any-grade hepatic toxicities with ipilimumab 3 mg/kg monotherapy is less than 4% and this increases to up to 15% when ipilimumab is dosed at 10 mg/kg. , The incidence of hepatitis is about 5% in patients treated with anti-PD-1 inhibitors only, but this increases to about 25% to 30% grade 3-15% in patients on combination ipilimumab and nivolumab.
Pancreatitis Associated With Immune Checkpoint Inhibitors
Reports of acute pancreatitis with ICIs are rare, whereas asymptomatic elevation of lipase and amylase are more common. Of note is the rare complication of autoimmune endocrine dysfunction of the pancreas with acute onset of type 1 diabetes.
Celiac Disease Associated With Immune Checkpoint Inhibitors
Rare irAE such as celiac disease have also been observed with ICI treatment presenting with nausea, vomiting, diarrhea or abdominal pain. Histological features include intraepithelial lymphocytosis, lymphoplasmacytic inflammation of the lamina propria, villous atrophy and crypt hyperplasia on small bowel biopsy. A gluten-free diet is a reasonable strategy for these patients (either alone or in combination with immunosuppression).
Mechanism of Immune Checkpoint Inhibitor–Mediated GI and Hepatic Manifestations
Biomarkers Predictive of GI irAE.
A study with 162 advanced melanoma patients with pretreatment blood samples for biomarkers showed higher baseline levels of immune-related genes (CD3E, IL2RG, CD4, CD37, IL-32, and RAC-2), cell-cycle associated genes (SPATAN1, BANF1, BAT1, PCGF1, FP36L2, and WDR1) and genes involved in vesicle trafficking (PICALM, SNAP23, and VAMP3) in patients who developed GI irAEs compared to those who did not. Biomarkers were also studied 3 weeks after treatment with ICIs; CD177, a unique neutrophil surface marker that plays an essential role in neutrophil activation and also mediates migration, was noted to be elevated. Carcino-embryonic antigen-related cell adhesion molecule (CEACAM), an adherence mediator important in neutrophil migration, was also found to be significantly increased in the GI irAE group. Another inflammatory cytokine, IL-17, has also been proposed as a predictor of irAEs, and has been correlated with the development of grade 3 GI toxicities.
Role of the Gut Microbiome.
The gut microbiome has been implicated in the response to ICI therapy. This holds significant promise as fecal transplants in addition to ICI therapy may play a role in enhancing therapy. Fecal abundance of Bacteroides fragilis negatively correlated with tumor size following CTLA-4 blockade. Interestingly, as the B. fragilis polysaccharide capsule is known to induce IL-12–dependent TH1 immune responses, these immunogenic bacteria show potential to act as “anticancer probiotics.”
The gut microbiota plays an important role in maintaining mucosal tolerance by promoting T-regulatory cell expansion or by stimulating anti-inflammatory cytokines. The intestinal microbial composition was sampled in a prospective study from 34 melanoma patients prior to CTLA-4 blockade. Although the patients all shared a similar proportion of Firmicutes , the Bacteroidaceae family was underrepresented in patients who later developed immune-mediated colitis. Bacteroidetes exert anti-inflammatory effects through various pathways. The combination of (1) polyamine transport system and (2) the biosynthesis of vitamins riboflavin (B2), pantothenate (B5), and thiamine (B1) resulted in 70% sensitivity and 83% specificity for predicting patients at risk of developing colitis. Thus, the microbiome may play a role in developing immune-related colitis. Further supporting this hypothesis is the observation that intestinal reconstitution of germ-free mice with the combination of B. fragilis and Burkholderia cepacia reduced histopathological signs of colitis.
Histological Presentation
Diarrhea and Colitis
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Anti-CTLA-4: Colitis seen after anti-CTLA-4 inhibitors is characterized by the presence of neutrophilic inflammation with increased intraepithelial lymphocytes, crypt epithelial cell apoptosis, and few or no features of chronicity.
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Anti-PD-1: Two patterns of colitis are seen following the use of anti-PD-1: active colitis (active inflammation, neutrophilic crypt micro-abscesses, increased crypt epithelial cell apoptosis, and presence of crypt atrophy/dropout) or lymphocytic colitis (increased intraepithelial lymphocytes in surface epithelium, surface epithelial injury, and expansion of the lamina propria). Similar histological changes can also be observed outside of the colon in the duodenum, stomach, and/or small bowel. Features of inflammatory bowel disease (IBD)-type chronicity are seen in patients with recurrent anti-PD-1 colitis, which may develop many months after stopping anti-PD-1 therapy.
Nausea/Vomiting/Epigastric Pain.
Patchy chronic duodenitis or chronic gastritis with rare granulomas can be seen. These findings suggest the possibility of immune mechanisms which are directed towards region-specific epitopes.
Hepatitis.
Liver biopsies of patients on ICIs, reveal a pan-lobular active hepatitis with a predominant CD8-positive inflammatory infiltrate, and hence, the pathological presentation mimics autoimmune hepatitis, and suggests underlying injury to hepatocytes. The cytotoxic T cell infiltrate can also result in injury to the bile ducts, manifesting as mild portal mononuclear infiltrate around the proliferated bile ductules.
BISPECIFIC ENGAGER OF T CELL ACTIVITY/BLINATUMOMAB
Blinatumomab is a bispecific antibody that belongs to a class of agents, which work as engagers of T cell activity via binding to CD19 and CD3. The drug is approved for relapsed or refractory B-precursor ALL. It is administered as a 4-week continuous infusion. Blinatumomab infusion is associated with cytokine release syndrome (CRS), which is a potentially life-threatening systemic inflammatory reaction observed after infusion of agents targeting different immune effectors and also with hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). The frequency of grade 3 or higher CRS ranged from 2% to 6% in clinical trials in adult patients with relapsed/refractory ALL, and was 6% in a trial conducted in children. Fortunately, CRS is fatal in a very small number of patients. The syndrome manifests with symptoms of fever, chills, hypotension, and tachycardia during or immediately after drug administration.
GI, Hepatic, and Pancreatic Manifestations of Blinatumomab
Blinatumomab can present with a broad spectrum of constitutional and organ-related disorders, and numerous blood test abnormalities. Patients present with nausea, vomiting, diarrhea, and hepatotoxicity (grade ≥3 increased ALT and AST in 9%–16% cases). ,
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Cases of pancreatitis have been reported during blinatumomab treatment; this has been observed mostly during clinical trials. It is important for physicians to be alert, and monitor amylase and lipase if clinically indicated.
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HLH/MAS has also been observed in patients receiving blinatumomab infusion.
Mechanism of Blinatumomab-Mediated GI and Hepatic Toxicities
The two blinatumomab-mediated mechanisms for hepatotoxicity are CRS and HLH/MAS.
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CRS is characterized by an increase in inflammatory cytokine release after the activation and cytotoxic damage of monocytes, macrophages, and different lymphocyte populations. This is associated with extensively high levels of IL-6, which plays a central role in the pathophysiology of these toxicities. Other effects that could be mediated by the release of cytokines include nausea/vomiting and increased AST/ALT levels. The increase in cytokine levels coincides with the early peak in the adverse events’ incidence and the development of severe peripheral B lymphocytopenia within days of blinatumomab initiation.
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HLH is a rare condition characterized by inappropriate immune activation and cytokine release that typically presents with fever and splenomegaly in association with hyperferritinemia, coagulopathy, hypertriglyceridemia, and cytopenias.
ADOPTIVE CELLULAR THERAPY (CAR T CELL AND T CELL RECEPTOR GENE THERAPIES)
Cellular immunotherapy consists of autologous or allogenic T cells which have been genetically engineered to express CARs or T cell receptors (TCRs) to redirect cytotoxicity specifically towards cancer cells. These therapies are currently emerging as a promising modality for a broad range of cancers. In August 2017, the FDA approved the first anti-CD19 CAR T cell product, tisagenlecleucel, for the treatment of pediatric and young adult patients with relapsed and/or refractory B-cell precursor ALL. Currently, novel targets such as CD20, NY-ESO-1, and B-cell maturation antigens, are being explored with CAR-based and TCR-redirected cell therapies in preclinical studies and early phase clinical trials, in hematological and non-hematological malignancies. The release of the multitude of chemokines and cytokines results in CRS with diverse manifestations including different organ systems, such as cardiovascular, respiratory, integumentary, GI, hepatic, renal, hematological, and nervous system, and manifests as high fever, hypotension, hypoxia, and/or multiorgan toxicity. There is a high risk of development of CRS in patients with bulky disease.
GI and Hepatic Manifestations With CAR T-Cell Therapy
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The GI and hepatic manifestations of CRS include nausea, vomiting, diarrhea (GI), and increased AST, ALT, or bilirubin levels (hepatic), which are reversible with CRS resolution. In a phase I clinical trial of axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma by Neelapu et al., the incidence of any grade nausea was 58%, any grade anorexia and grade 3 or higher anorexia was 50% and 2%, respectively; any grade diarrhea and grade 3 or higher diarrhea was 43% and 4%, respectively; and any grade vomiting and grade 3 or higher vomiting was 34% and 1%, respectively. Phase I results of the ZUMA-1 study showed that 1/7 patients (14%) developed grade 3 or higher ascites and one in seven patients (14%) developed grade 3 AST elevation. There are studies which have shown that high serum levels of IL-6, soluble gp 130, IFN-γ, IL-15, IL-8, and/or IL-10, either 1 day before or 1 day after CAR T cell infusion, are associated with the subsequent development of CRS, but prospective validation is required for the above tests. The onset of symptoms of CRS toxicity is usually seen within the first week after treatment with CAR T cells and typically peaks within 1 to 2 weeks of cell administration.
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