have changed the treatment method of cancer;
two tables to clarify the toxic reaction of cancer immunotherapy !
This article summarizes
immunotherapy, the fourth pillar of cancer treatment
two tables, the main toxic reaction is clear at a glance
nine flowers bloom, counting toxic reactions
1 Immune therapy, the fourth pillar of cancer treatment
Figure 1 The fourth pillar of cancer treatment
immune checkpoint inhibitor (Immune Checkpoint Inhibitor, ICI) and chimeric antigen receptor T cell immunotherapy (Chimeric Antigen Receptor T-Cell Immunotherapy, CAR-T), are known as the fourth pillar of cancer treatment after surgical procedures, radiation therapy, and anti-tumor chemical drug treatment. This evaluation was from the 2018 Nobel Prize in Physiology or Medicine. The awards for that year were shared by James P. Allison from MD Anderson Cancer Center and Tasuku Honjo from Kyoto University for their discovery of the role of inhibiting negative immune regulation in tumor treatment. Allison confirmed in 1996 that blocking cytotoxic T lymphocyte-associated antigen-4 (CTLA-4, CD152) could enhance the antitumor response of T cells [2]; Honjo identified and cloned programmed death 1 (programmed death 1, PD-1, CD279) [3] in 1992. These two targets opened the beginning of tumor immunotherapy, and new derivative drugs are still being developed, tested and marketed... (Click to view: What is the Nobel Prize in 2018? Where is the god of immunotherapy?)
Figure 2 2018 Nobel Prize winner in Physiology or Medicine
At the same time, although CAR-T cell therapy has not won the Nobel Prize, it has made a fortune for itself with its practical efficacy, and together with ICIs, it has changed the treatment of various solid tumors and hematologic malignant tumors. In addition, the research and development of oncolytic viruses and cancer vaccines is also thriving. However, this treatment method is not perfect and the toxic reaction is inevitable. Among the toxic reactions related to
immunotherapy, we have encountered some of them in chemotherapy before, but there have been many toxic reactions that have not been heard of in the previous generation. Even the name is not smooth, let alone diagnosis and treatment. These cancer immunotherapy-related toxic reactions often require close monitoring and specific management methods, including the use of hormone drugs or immunomodulators.
Figure 3 Guidelines for the management of toxic reactions related to immunotherapy
The National Comprehensive Cancer Network (NCCN), the European Society of Oncology (ESMO), the American Society of Clinical Oncology (ASCO), and the American Society of Tumor Immunotherapy (SITC) have all formulated management guidelines for the treatment of toxic reactions of ICIs and CAR-T cells [4-7], and the God-Journal of CA has started this time from pathophysiology to clinical manifestations, diagnostic methods and management methods, and called for further research on related risk stratification models to continuously improve the control of these toxic reactions [8].
Figure 4 The Gods CA tells you what to do when immunotherapy encounters a toxic reaction
2 Summary of the two tables, the main toxic reactions are clear at a glance
Immunotherapy mainly includes ICIs and CAR-T cell therapy. The unique anti-cancer mechanism leads to many toxic reactions of this therapy.
Figure 5 CTLA-4 and PD-1-related anti-tumor mechanisms
For example, high-dose interleukin-2 (IL-2) used to treat advanced melanoma and renal cell carcinoma may trigger multiple downstream reactions of T cells and natural killer (NK) cells, leading to capillary leakage and sepsis-like syndrome, and even multi-organ failure; ICIs may inhibit the anti-tumor function of T cells, leading to organ-specific inflammation or immune-related adverse reactions (irAE); CAR-T cell therapy, mainly used for the treatment of hematologic malignant tumors, may cause cytokine release syndrome (CRS) or immune effector cell-related neurotoxic syndrome (ICANS). The main toxic reactions of these two treatments are summarized for us through two tables in the review.
Table 1 Main toxicity reactions of immune checkpoint inhibitors
Table 2 Main toxicity reactions of chimeric antigen receptor T cells
However, these two tables are actually not complete enough; to know the details, you need to continue reading!
3: Nine flowers bloom, counting toxic reactions without being tight or slowly
Summary of the review of nine cancer immunotherapy-related irAEs for us, among which there are seven toxic reactions related to ICIs, including skin toxic reactions, gastrointestinal toxic reactions (diarrhea or colitis , hepatitis), endocrine toxic reactions (thyroid, pituitary), pneumonia, rheumatic toxic reactions, rare immune-related adverse reactions (neurotoxicity, nephrotoxicity, eye toxicity, cardiovascular toxicity, hematological toxicity), and finally discuss patients with autoimmune diseases or have previously had immune-related adverse reactions; toxic reactions related to CAR-T cell therapy mainly emphasize two types, namely CRS and ICANS.
▍1/ Skin toxicity
Skin toxicity is the most common toxic reaction of CTLA-4 or PD-1/PD-L1 inhibitors. It has various manifestations, including maculopapular/papule rash, skin hypersensitivity reaction, dermatomyositis, Sweet syndrome, pyoderma gangrene, bullous disease, drug reaction with eosinophilia and systemic symptoms (DRESS), photosensitive reaction, bullous disease, psoriasis, etc. It can also cause vitiligo in patients with melanoma .
When combined with ICIs, more severe and earlier skin toxic reactions may occur, such as Stevens-Johnson syndrome/toxic epidermal necrolysis, etc. Treatment mainly includes emollient, glucocorticoid , oral antihistamines, or inviting dermatologists to deal with it.
▍2/ Gastrointestinal toxicity reactions
Gastrointestinal toxicity reactions include diarrhea/colitis and hepatitis.
Diarrhea/colitis: Diarrhea/colitis is also a common complication of ICIs treatment, among which patients receiving CTLA-4 inhibitors are more likely to experience this complication; combined with CTLA-4 and PD-1 inhibitors, it may increase the risk of grade 3/4 colitis.
For diarrhea/colitis of grade 2 or above, ICIs should be suspended immediately and systemic glucocorticoid treatment should be initiated. If there is no significant effect after 3-5 days, infliximab should be considered. If the patient cannot tolerate infliximab, vedolizumab against intestinal integrin α4β7 may be considered. Early biotherapy may reduce the dosage and time of glucocorticoid use, but the timing of infliximab and vedolizumab remains to be further evaluated.
Hepatitis: The incidence of hepatitis is lower than that of diarrhea/colitis, but the incidence rate will also increase when ICIs is combined. The most common manifestations are asymptomatic elevations of AST and ALT with or without hyperbilirubinemia. Most patients will disappear after treatment, but some patients will also experience acute liver failure. In addition to considering liver function abnormalities related to ICI treatment, other drugs, alcohol, infection, viral hepatitis and other causes need to be considered.
When the toxic reaction of patients with
is at level 2 or above, ICIs treatment should be suspended until they return to level 1 and then the treatment should be started; if the patient's liver function has not recovered after the suspension of treatment, glucocorticoids, or even mycophenolate mofetil should be started; if the clinical condition deteriorates sharply, antithymocyte globulin therapy can be considered.
▍3/ Endocrine toxicity
ICIs treatment includes hypothyroidism, hyperthyroidism, thyroiditis, hyperpituitary function, primary adrenal insufficiency and insulin-dependent diabetes. The symptoms of endocrine toxicity associated with ICIs treatment may not be specific, including nausea, fatigue, headache or weakness. Diagnosis of ICI-related endocrine toxicity requires preparation before the onset of medication, and thyrotropin and free thyroxine levels should be routinely checked at baseline and during treatment, and also consider testing for corticotropin and cortisol. Endocrine toxicity does not disappear with the end of treatment, but requires lifelong hormone replacement therapy, and treatment requires close cooperation with endocrinologists.
In ICI treatment, hypothyroidism is more common than hyperthyroidism, with the median occurrence time being at the 4th week after the start of treatment; patients with hypothyroidism should undergo thyroid hormone replacement therapy after eliminating adrenal insufficiency. Pituitary inflammation mainly occurs in anti-CTLA-4 treatment. Patients with clinical symptoms or laboratory results of pituitary hypofunction should undergo testing of thyroid, adrenal and gonadal axis functions, and need to cooperate with the endocrinology department for comprehensive treatment.
▍4/ pneumonia
Although the incidence of this toxic reaction is low, it is potentially life-threatening, so all patients with new respiratory symptoms should consider this possibility. 35% of the deaths related to anti-PD-1/PD-L1 treatment were related to pneumonia. The incidence of pneumonia with single-agent anti-PD-1 treatment was slightly higher than that of anti-CTLA-4 treatment, and the incidence of combined treatment was higher; lung cancer patients had more and more serious pneumonia after treatment than melanoma patients. Patients may experience symptoms such as cough, chest pain, wheezing, shortness of breath, hypoxia or fatigue, but some patients have no symptoms and are diagnosed by accident through imaging examinations.
For patients with respiratory symptoms during treatment, pneumonia should be highly suspected. Due to the possibility of concurrent immune inflammation and infection, it is recommended to use the broad-spectrum antibiotics and the immunosuppressant during treatment. For pneumonia of grade 2 or above, ICIs treatment should be stopped, and pulmonary consultations should be invited to undergo bronchial alveolar lavage or bronchoscopy, and large doses of glucocorticoid treatment may be initiated and hospitalization may be required. Infliximab, cyclophosphamide or mycophenolate for additional immunosuppression can be considered for glucocorticoid refractory pneumonia.
▍5/ Rheumatoid toxicity reaction
ICIs treatment rate of rheumatoid toxicity reaction has not been studied in depth. Patients can manifest serum-negative spondylitis, multiple arthritis, rheumatoid arthritis-like manifestations, conjunctivitis, uveitis, reactive arthritis, Sjogren's syndrome, myitis, multiple myitis-like manifestations, giant cell arteritis, rheumatoid polymyalgia, systemic lupus erythematosus and sarcoidosis. If the patient develops acute musculoskeletal symptoms, he should be highly suspected of having a rheumatic toxic reaction.
1 grade toxic reactions can be treated with nonsteroidal anti-inflammatory drugs, and prednisone can be considered if there is no improvement; toxic reactions of grade 2 or above should be treated with prednisone. For patients with poor glucocorticoid effects, other immunosuppressants can be considered, including methotrexate, sulfasalazine, leflunomide or anti-cytokine therapy, such as anti-IL-6 antibody tocilizumab, etc.
▍6/ Other rare immune-related adverse reactions:
includes neurotoxicity, nephrotoxicity, eye toxicity, cardiovascular toxicity, and hematologic toxicity.
Neurological toxicity: Neurological toxicity can be manifested as non-infectious encephalitis/myelitis, Guillen-Barre syndrome, myasthenia gravis, peripheral neuropathy, etc., and needs to be differentiated from infection, central nervous system metastasis or leponema metastasis, paraneoplastic syndrome, vitamin B12 deficiency and diabetic neuropathy.
For patients with grade 2 or above neurological symptoms, ICIs treatment should be stopped and glucocorticoids should be started while undergoing diagnostic evaluation, and neurology consultation should be invited. For patients with refractory glucocorticoids or patients with rapid progression, other immunosuppressive measures can be considered, including plasma replacement, immunoglobulin, anti-α4 integrin, natalizumab, etc.
Nephrotoxicity: Nephrotoxicity related to ICIs treatment is rare, and can be manifested as hypertension, electrolyte imbalance, changes in urine volume or increased creatinine, and often pathologically manifested as acute interstitial nephritis (AIN). Acute renal injury in patients treated with ICIs needs to be distinguished from nephrotoxicity caused by dehydration, sepsis and other drugs, and urine tests and renal ultrasound examinations. For patients with nephrotoxicity level 2 or above, ICIs treatment should be continued; if no other reason is caused, glucocorticoids can be given. However, the optimal dose and duration of glucocorticoids are not known. Eye Vitality: Eye Vitality associated with ICIs treatment is less common, and can be manifested as uveitis, peripheral ulcerative keratitis, Vogt-Koyanagi-Harada syndrome, choroidal neovascularization, melanoma-related retinopathy, thyroid-related eye diseases, and idiopathic orbital inflammation. Ocular toxicity often occurs simultaneously with extraocular toxicity, and is most often associated with colitis. Since adverse eye reactions may threaten vision, patients with visual symptoms should be referred immediately to the ophthalmology department. Treatmentally, the 2nd grade toxic reaction can be controlled by local glucocorticoids, while the 3/4th grade toxic reaction usually requires systemic glucocorticoid treatment. Cardiovascular toxicity: cardiovascular toxicity shows varying, such as dyspnea, chest pain and cardiovascular failure; cardiovascular toxicity reactions include myocarditis , pericarditis, heart fibrosis, arrhythmia and neo-onset heart failure. These toxic reactions can be fatal and need to be vigilant.
recommends that all patients should undergo baseline electrocardiogram and troponin assay; patients with cardiovascular toxicity should undergo electrocardiogram, troponin, brain natriuretic peptide, echocardiogram and chest X-ray; patients with suspected myocarditis should receive cardiology consultation as soon as possible; patients diagnosed with myocarditis should stop ICIs treatment and use high-dose glucocorticoid treatment; patients who are ineffective in glucocorticoid therapy should consider additional immunosuppression, such as infliximab, antithymocyte globulin, immunoglobulin, mycophenolate and tacrolimus, etc.
Hematologic toxicity: Hematologic reactions are rare, but they show a variety of manifestations, including hemolytic anemia, erythrocyte insufficiency, neutropenia, thrombocytopenia, thrombocytopenia, myelodysplasia, hemophilia A, aplastic anemia and hemophagocytosis syndrome, etc., which need to be distinguished from cancer progression, bone marrow involvement, gastrointestinal bleeding and drug effects. In addition to inviting hematology consultations, it is recommended to use glucocorticoid alone. ▍7/ Patients with autoimmune diseases or patients with history of toxic reactions
Such patients may experience worsening of autoimmune diseases and reappearance of the original/new toxic reaction. The pathophysiological mechanisms and severity of toxic reactions in these patients differ greatly, and long-term prospective studies are needed to clarify the optimal treatment in a given clinical setting.
In addition to the endocrine toxicity that can be restored with hormone replacement therapy, it is recommended to permanently stop ICIs treatment after a grade 4 toxic reaction occurs; ICIs treatment should also be permanently stopped after a grade 3 toxic reaction with a high risk of death. Patients with autoimmune diseases or a history of toxic reactions can receive ICIs, but the pros and cons need to be fully evaluated and carried out under close multidisciplinary cooperation.
▍8/ Cytokine Release Syndrome (Cytokine Storm):
CRS is a systemic inflammatory response caused by T cell activation after binding to CAR-T cells and is the most common toxic reaction after infusion of CD19 CAR-T cells. Activated T cells can produce cytokines and chemokines such as IL-2, IL-2R-α, IFN-γ, IL-6, IL-6R and granulocyte-macrophage colony stimulating factor (GM-CSF). Surrounding immune cells, such as monocytes, macrophages and dendritic cells, also produce cytokines, which will enable the full activation of the immune system. The diagnosis of CRS requires fever first, and other nonspecific symptoms include discomfort, myalgia, fatigue, and rash.
CRS can be self-limiting or can be relieved under supportive treatment, but pulmonary edema, hypotension, , multi-organ failure, circulatory failure, and ultimately life-threatening. The occurrence of CRS can occur 1-14 days after CAR-T cell infusion. Patients with severe CRS may experience symptoms similar to hemophagocytosis/macrophage activation syndrome, including hepatosplenomegaly, hepatic insufficiency, hyperferritinemia, hypofibrinogen and coagulation disorders. These symptoms need to be distinguished from other causes of fever, hypotension and respiratory failure, including infection and tumor progression.
The National Comprehensive Cancer Network and the American Society for Transplant and Cell Therapy (ASTCT) graded CRS mainly based on the severity of hypotension and hypoxia, which determines subsequent treatment. For patients with grade 1 CRS, broad-spectrum antibiotics should be initiated while performing other examinations and diagnosis, and corresponding supportive treatment should be performed. Patients with CRS of grade 2 or above should receive intravenous tocilizumab at 8 mg/kg body weight; patients with Grade 2 CRS and Grade 3/4 CRS who still have persistent hypotension after anti-IL-6 treatment should take glucocorticoids. Tocilizumab has been shown to rapidly inhibit CRS caused by CAR-T treatment, but the best time to use is still being explored.
▍9/ Immune effector cell-related neurotoxic syndrome
ICANS may manifest as a variety of neurological symptoms, initially tremor, writing disorder, mild expression aphasia, apnea and inattention, among which expressive aphasia is a unique symptom of ICANS. ICANS may be associated with the expansion of cytokines into the central nervous system or the transport of CAR-T cells to the central nervous system, but the specific pathophysiological mechanism remains unclear. Risk factors for ICANS include young, B-cell lymphocytic leukemia, high tumor burden, and higher CAR-T cell doses.
American Society for Transplantation and Cell Therapy [9] has issued consensus guidelines on recommendations for standardized ICANS grading. Through brain MRI, EEG, and neurology consultation, the neurotoxicity related to CAR-T treatment is objectively evaluated, and the effects of drugs that may have sedative effects are excluded. ICANS usually does not respond to tocilizumab. Guidelines recommend the use of high-dose glucocorticoids in patients with grade 2 or above; however, tocilizumab should be added if CRS is present.
Cancer immunotherapy, including ICIs and CAR-T cell therapy, has changed the treatment of a variety of solid tumors and hematologic malignant tumors, and the ongoing clinical trials have further expanded the scope of application of these treatments.
With the continuous promotion of immunotherapy, it is necessary to have a deeper understanding of its unique toxic reactions to help medical staff reasonably respond to and manage these toxic reactions during treatment. At the same time, it is necessary to further find the risk factors for patients to experience these toxic reactions and explore the pathophysiological mechanisms behind them, so as to lay the foundation for better prevention and treatment of these toxic reactions. Now, the most important treatments for these toxic reactions are glucocorticoids and immunosuppressants. In addition, there are currently studies that are evaluating the effect of immunosuppression on the anti-tumor efficacy of immunotherapy.
References
[1] Nobelförsamlingen The Nobel Prize Assembly at Karolinska Institutet. The Nobel Prize in Physiology or Medicine 2018, Advanced Information. Avaliable at:
http://www.nobelprizemedicine.org/wp-content/uploads/2018/10/Adv_info_2018.pdf 2020-01-22.
[2] Leach DR, Krummel MF, Allison JP. (1996). Enhancement of Antitumor Immunity by CTLA-4 Blockade. Science. 1996 Mar 22;271(5256):1734-6.
[3] Ishida Y, Agata Y, Shibahara K, et al. (1992). Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992 Nov;11(11):3887-95.
[4] Thompson JA. New NCCN Guidelines: Recognition and Management of Immunotherapy-Related Toxicity. J Natl Compr Canc Netw. 2018;16(5S):594–596. doi:10.6004/jnccn.2018.0047.
[5] Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(Suppl 4):iv264–iv266. doi:10.1093/annonc/mdy162.
[6] Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36(17):1714–1768. doi:10.1200/JCO.2017.77.6385.
[7] Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immuno checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer. 2017;5(1):95. Published 2017 Nov 21. doi:10.1186/s40425-017-0300-z.
[8] Kennedy LB, Salama AKS. A review of cancer immunotherapy toxicity [published online ahead of print, 2020 Jan 16]. CA Cancer J Clin. 2020;10.3322/caac.21596. doi:10.3322/caac.21596.
[9] Lee DW, Santomasso BD, Locke FL, et al. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019;25(4):625–638. doi:10.1016/j.bbmt.2018.12.758.
This article was first published: Medical Tumor Channel
Author of this article: Whale
Editor: Sharon
Copyright Statement
Original of this article If you need to reprint, please contact the authorized
- End -
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-