There has been significant improvement in the outcome of many malignancies, which have required balancing anti-tumor immunity and immune toxicity.
FROM THE ACADEMY OF CONSULTATION-LIAISON PSYCHIATRY
The immune system has an essential underlying role in both physiological and pathological conditions. The immune response is the result of the complex interaction of inflammatory cells and circulating humoral factors, which trigger immune surveillance, immune defenses, and the healing processes that are crucial for survival.
In recent years, immunotherapies have become increasingly effective options for cancer treatment, but they can also lead to abnormal immune reactions and adverse effects ranging from minor to severe toxicities against crucial organ systems, including the brain. Cancer immunotherapy was first attempted with nonspecific immune stimulation using Bacillus Calmette-GuÃ©rin (BCG) or vaccination against other infectious agents with limited success. Treatment with immune modulating cytokines such as interleukin and interferon proved effective, and identification of tumor specific antigens led to attempts at active immunization of the patient with better results. The newer methods of adoptive cell transfer and blockade of immune checkpoints show additional promise.
Traditional cytotoxic chemotherapy is the most commonly used and generally most effective class of antineoplastic agents. It acts by targeting rapidly dividing malignant cells. The adverse effects of chemotherapy are related to antimetabolic effects on normal cells while simultaneously targeting the malignant cells. Immunotherapy can often bypass these toxicity problems and may be more effective in selected patients, but it can also result in its own toxicity, including adverse neuropsychiatric consequences.
The immune system normally detects cancer by recognizing antigens expressed by cancer cells but not by normal cells. These tumor-associated antigens may be tumor-specific antigens uniquely expressed on cancer cells, or they may be neoantigen (ie, new antigens that result from mutations in cancer cells). When tumor specific antigens and neoantigens are detected, they are regarded as foreign by the patient’s immune surveillance mechanisms, and elicit anti-tumor immune responses.
The prognosis is usually considered to be better when an inflammatory reaction is present in tumor tissues, which indicates the presence of immunity to the tumor. When the patient’s immune system attack on the tumor cells has eliminated the most highly immunogenic cancer cell clones, less immunogenic malignant cells remain, which can multiply relatively undisturbed. By the time of diagnosis, most cancers no longer have evidence of an inflammatory response, indicating a poorer prognosis.
This article is a brief introduction to the immunotherapy of malignancy for psychiatrists who may encounter patients who have received these newer immune-mediated therapies for cancer as well as for the consultation-liaison psychiatrists who are more likely to encounter patients who have been exposed to an array of immunotherapy options and their potential adverse consequences. It is important for psychiatrists to be aware of the potential neuropsychiatric toxicities and complications to be able to distinguish them from primary psychiatric disorders and to be able to address them when they occur.
Tumor associated antigens
Identification of human tumor-associated antigens has led to antigen specific immunotherapy using these antigens as targets for monoclonal antibodies and cancer vaccines. Specific monoclonal antibodies have been developed against a variety of molecular targets expressed on different cancer cells. These anti-tumor antibodies represent autoimmunity and can also react against normal cells or can present like paraneoplastic neurologic disorders.
Antigens used in cancer vaccines usually include peptides and whole proteins with adjuvants to improve immunogenicity. For example, glypican-3 (GPC-3) is a carcinoembryonic antigen overexpressed in human hepatocellular carcinoma. Vaccination with GPC3-derived peptide has shown clinical benefits and a peptide specific immune response that is predictive of overall survival.1
Tumor associated antigens have also been encoded in recombinant viruses in an attempt to generate a more robust immune response to the tumor antigens. As it became easier to identify tumor specific and neoantigens from individual cancer patients, it was hoped that vaccines that target them could be developed for personalized anti-cancer immunization therapy. Unfortunately, cancer vaccine trials frequently report immunologic responses without any clinical benefit.
Cytotoxic chemotherapy is typically immunosuppressive because immune cells rapidly divide and are vulnerable to chemotherapy’s cytotoxic effects. There is often a period of shrinkage or limited growth of the tumor after chemotherapy is started, followed by possible resistance to the chemotherapeutic drug, stimulating tumor growth and metastases. Tumor cell death can reactivate antitumor immunity and restore immunosurveillance, which suggests the anticancer activity of chemotherapy by both cytotoxicity and immune mechanisms.
Many of the functions of the immune system are mediated through the production of small proteins called cytokines. These proteins include interleukins, interferons, and tumor necrosis factor. Cytokines modulate the highly complex, interrelated inflammatory response depending on clinical, physiological, and immune factors. Chemokines are locally acting cytokines that enhance the migration of inflammatory cells, and lymphokines are mediators that are produced transiently during an immune response.
Cytokines have major effects on cerebral function and affect sleep patterns, mood, behavior, cognition, and memory. Cytokines can inhibit acetylcholinergic pathways, resulting in delirium. Interleukins 1 and 2 (IL-1, IL-2), interferon (IFN), and tumor necrosis factor (TNF) can trigger excitatory CNS effects including agitation, delirium, delusions, hallucinations, and seizures.2 Patients receiving IL-2 or IFN-Î± for cancer treatment have experienced hypotension, multiorgan failure, and severe neurotoxicity with cognitive, behavioral, and mood symptoms.3
IFN-Î± has been used for over 30 years to treat myeloproliferative disorders. It can induce cell differentiation and cell death, and it can inhibit cell proliferation and angiogenesis required for tumor growth.4 IFN-Î± therapy for cancer has been associated with autoimmune disorders of vitiligo and diabetes and can aggravate preexisting autoimmune disease.5 Although IFN-Î±2 can be an effective anticancer agent, its use has been limited by its toxicities.
IL-2 is a cytokine that plays a major role in the growth and proliferation of immune cells. Trials of high dose IL-2 to treat a variety of disorders, including malignancy, began in 1985 and IL-2 has proved to be an important immunotherapy cytokine for the treatment of cancer.6,7 IL-2 induces activation of lymphocytes and their differentiation into lymphokine-activated killer cells, which can recognize and eliminate tumor cells. By inducing systemic inflammation, IL-2 can exacerbate autoimmunity or trigger it de novo. Nebulized and aerosolized IL-2 has enabled localized delivery directly to the lungs resulting in less systemic effects, higher local immune cell activation, and greater antitumor effect in patients with primary lung cancer and pulmonary metastases.6
The use of IL-2 has been limited by systemic toxicities, including the capillary leak syndrome (CLS). It can occur following administration of cancer drugs, bone marrow transplant, and IL-2.8 In patients with CLS, fluid from the circulatory system leaks into the interstitial space and results in edema, hypotension, hypoalbuminemia, hemoconcentration, dyspnea, circulatory shock, cardiopulmonary collapse, and multiple organ failure. Prophylactic pretreatment with intravenous immunoglobulin and supportive therapy with careful fluid management are of clinical benefit when CLS occurs.
Adoptive cell therapy
Adoptive cell therapy is based on infusions of autologous T cells to mediate an antitumor response. Chimeric Antigen Receptors (CARs) are synthetic receptors for T-cell antigens that redirect the specificity and reprogram the function of the T cells onto which they are genetically introduced. Chimeric antigen receptor T cells (CAR-T) are the patient’s own T cells modified using viral vectors to express these CARs.
CAR-T cells were first made in 1993 and represent a form of adoptive cell therapy. To make CAR-T cells, lymphocytes are harvested from a tumor biopsy or a resected tumor. These lymphocytes are then grown in vitro with IL-2 and reinfused into the patient after the patient’s T-regulatory cells are eliminated. The infused CAR-T cells retain their cytotoxic activity and recognizing tumor antigens, eliminate the malignant cells.
Currently, CAR-T cells are usually CD19 specific, and they target and lyse CD19 positive cells in both normal and malignant B cell lineages. CD19 is a cell surface antigen unique to B-cells, thus specifically targeting CD19 is effective for B-cell leukemias and lymphomas even in patients with a high tumor burden. Moreover, treatment with CAR-T cells has yielded high remission rates in patients with other refractory, relapsed disease, including acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma.9
Adverse events following infusion of CAR-T cells are reversible in most instances, although they often require specific medical intervention and transfer to intensive care for support and management. The most common adverse effect is cytokine release syndrome (CRS). It typically begins within the first week after T-cell infusion and follows the in vivo proliferation of the infused CAR-T cells.
CRS occurs in 13% to 43% of patients and is characterized by high fever, cardiac dysfunction, hypotension, dyspnea, respiratory compromise, hypoxia, and multiorgan failure. The severity of CRS may range from mild to severe life-threatening multiorgan failure. Corticosteroids are considered the main treatment for CRS, but they are toxic to infused CAR-T cells, which limits the outcome of CAR-T treatment as well as the efficacy of corticosteroid treatment itself.
Rarely, severe CRS can evolve into fulminant hemophagocytic lymphohistiocytosis. It is related to tumor burden and cell lysis and is associated with elevated levels of inflammatory markers such as ferritin, C-reactive protein, lactate dehydrogenase, IFN-Î³, soluble IL-2 receptor, and IL-6.
Neurologic toxicity is the second most common toxicity associated with CAR-T therapy. It is distinct from CRS and has been termed “CAR-T-cell-related encephalopathy syndrome (CRES).” It appears to result from endothelial dysfunction and increased blood brain barrier permeability, and is associated with headache, seizures, confusion, agitation, delirium, hallucinations, aphasia, and myoclonus, and may require hospitalization in an intensive care unit. The management of CRES neurotoxicity has been non-specific, generally emphasizing supportive care. Antipsychotics are effective for agitation, delirium, and psychotic symptoms associated with CRES.
New engineering modalities may further enhance the efficacy and safety of CAR-T cells. Modifications in the way CARs are made to allow destruction of CAR-T cells when serious toxicity occurs have been suggested, but they have increased the risk of graft-versus-host disease.9 Recent FDA approval of CD19 CAR-T cells for acute lymphoblastic leukemia and non-Hodgkin lymphoma will likely lead to expanded use of these therapies to physicians without prior experience in managing toxicities, increasing risks of adverse consequences and problems in management.
Melanoma antigen gene (MAGE) proteins are a large group of proteins expressed in reproductive tissue and a wide variety of cancers. These proteins are associated with aggressive cancers, a worse clinical prognosis, increased tumor growth, and increased metastases.10 Adoptive cell therapy using autologous anti-MAGE-A3 engineered T cells has been attempted. The patients experienced clinical regression of their cancers, but Parkinson-like symptoms and mental status changes were noted, and a few patients lapsed into coma and subsequently died. MRI showed perivascular leukomalacia, and autopsy showed necrotizing leukoencephalopathy with extensive white matter defects, widespread neuronal cell destruction and lymphocyte infiltration in the brain parenchyma.3
Immune checkpoint inhibitors
Immune checkpoints are normal inhibitory signals in the immune system that maintain self-tolerance and modulate immune response. Cancer cells can bypass immune checkpoints and immune surveillance, which interferes with the patient’s normal immunologic ability to recognize and destroy cancer cells. Checkpoint inhibitors are monoclonal antibodies that block specific immune checkpoint molecules that antagonize immune inhibitory pathways and promote immune activation by removing or blocking the inhibitory signals. Immune checkpoint inhibition has been effective and safe in patients with solid tumors and some hematologic malignancies, resulting in both long-lasting tumor responses and adverse effects.11
The most prominent checkpoint blocking target is cytotoxic T-lymphocyte-associated protein-4 (CTLA-4).12 CTLA-4 is a potent inhibitor of T-cell activation that helps maintain self-tolerance. Anti-CTLA-4 antibodies result in activation of T-cells and initiate an anti-tumor response. While the therapeutic blockade of CTLA-4 enhances anti-tumor immunity, it may also inadvertently increase the likelihood of paraneoplastic neurologic disorders due to antibodies against tumor associated antigens that cross react with neurologic cells.
Most adverse effects of CTLA-4 blockade usually resolve after several weeks. Mild liver and gastrointestinal effects respond to steroids, and mild dermatitis is usually managed by antihistamines, but more severe intestinal perforation and toxic epidermal necrolysis have been described.3 Endocrinopathies associated with CTLA-4 blockade occur with either hormone excess or deficiency, and one or more endocrine glands can be affected sequentially or simultaneously. They are mostly irreversible and require long-term hormone therapy.
Programmed cell death protein 1 (PD-1) is an immune checkpoint regulator that helps prevent auto-immunity and uncontrolled inflammation in chronic infections.13 Inhibition of PD-1 has been used to treat melanoma, lung cancer, and renal cell carcinoma. Adverse effects include fatigue, pruritis, rash, diarrhea, colitis, and pneumonitis.
Checkpoint inhibitors are associated with a unique group of autoimmune toxicities called “immune-related adverse events.” These include neutropenia, thrombocytopenia, red cell aplasia, hemophilia A, orbital inflammation, uveitis, keratitis, lupus nephritis as well as a range of potentially severe neurologic toxicities the affect the central and peripheral nervous system including myositis, myasthenia gravis, Guillain-Barre, and encephalitis with altered mental status. These conditions are usually responsive to corticosteroids, plasmaphoresis, and IV immunoglobulin.
There has been significant improvement in the outcome of many malignancies from increased understanding and application of the anti-tumor immune system and subsequent development of new immunotherapy approaches, which have required balancing anti-tumor immunity and immune toxicity.
Acknowledgement- The authors acknowledge the Academy of Consultation-Liaison Psychiatry for helping to bring this article to fruition. The Academy is the professional home for psychiatrists providing collaborative care bridging physical and mental health. Over 1200 members offer psychiatric treatment in general medical hospitals, primary care, and outpatient medical settings for patients with comorbid medical conditions.
Dr Charoensook is Senior Fellow, Child-Adolescent Psychiatry, Los Angeles County-University of Southern California Medical Center and Dr Turkel is Attending Psychiatrist, Children’s Hospital Los Angeles, Emerita Associate Professor of Psychiatry and the Behavioral Sciences, University of Southern California Keck School of Medicine, Los Angeles, CA.
The authors report no conflicts of interest concerning the subject matter of this article.
1. Tada Y, Yoshikawa T, Shimomura M, et al. Analysis of cytotoxic T lymphocytes from a patient with hepatocellular carcinoma who showed a clinical response to vaccination with a glypican-3-derived peptide. Int J Oncol. 2013;43:1019-1026.
2. Dunlop RJ, Campbell CW. Cytokines and advanced cancer. J Pain Symp Manage. 2000;20:214-232.
3. Gangadhar TC, Vonderheide RH. Mitigating the toxic effects of anticancer immunotherapy. Nat Rev Clin Oncol. 2014;11:91-99.
4. Miwa S, Shirai T, Yamamoto N, et al. Current and emerging targets in immunotherapy for osteosarcoma. J Oncology. 2019. https://www.hindawi.com/journals/jo/2019/7035045/. Accessed March 12, 2019.
5. Amos SM, Duong CPM, Westwood JA, et al. Autoimmunity associated with immunotherapy of cancer. Blood. 2011;18:499-509.
6. Dhupkar P, Gordon N. Interleukin-2: old and new approaches to enhance immune-therapeutic efficacy. Adv Exp Mol Biol. 2017;995:35-51.
7. Koury J, Lucero M, Cato C, et al. Immunotherapies: exploiting the immune system for cancer treatment. J Immunol Res. 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5872614/. Accessed March 6, 2019.
8. Jeong GH, Lee KH, Lee IR, et al. Incidence of capillary leak syndrome as an adverse effect of drugs in cancer patients: a systematic review and meta-analysis. J Clin Med. 2019;8:143-163.
9. Perales M-A, Kebriaei P, Kean LS, Sadelain M. Building a safer and faster CAR: seatbelts, airbags, and CRISPR. Biol Blood Bone Marrow Transplant. 2018;24:27-31.
10. Weon JL, Potts RP. The MAGE protein family and cancer. Curr Opin Cell Biol. 2015;37:1-8.
11. Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139-148.
12. Pitt JM, VÃ©tizou M, DaillÃ¨re R, et al. Resistance mechanisms to immune-checkpoint blockade in cancer: tumor-intrinsic and -extrinsic factors. Immunity. 2016;44:1255-1269.
13. Tsirigotis P, Savani BN, Nagler A. Programmed death-1 immune checkpoint blockade in the treatment of hematologic malignancies. Ann Med. 2016;48:428-439.