Brief introduction to immunotherapy
Immune-based therapies have emerged as a promising modality in cancer treatment. These therapies use the body’s immune system to fight cancer by harnessing the antitumor properties of the host immune system to eliminate the cancer. Several types of immunotherapy exist and can be broadly categorized into:
- 1.
Cancer vaccines
- 2.
Adoptive cell transfer therapies such as those using chimeric antigen receptor T-cells (see Chapter 30 on CAR T-cell therapies)
- 3.
Immune checkpoint inhibitors (ICIs)
Cancer vaccines deliver a tumor-specific neoantigen or many tumor-associated antigens that are recognized by the host immune system and enhance the antitumor immune response. Adoptive cell transfer utilizes a host’s T-cells, which are typically harvested by leukapheresis and enhanced ex vivo to make them more reactive to tumor-specific antigens. Chimeric antigen receptor (CAR) T-cells are a prototypical example where a patient’s T-cells are collected and genetically modified to express a modified chimeric antigen receptor that traffics to the tumor, generates an antitumor cytolytic effect, or releases cytotoxins that induce cancer cell death when infused back into the patient.
This chapter focuses on the third category of immunotherapies, immune checkpoint inhibitors, which target the interaction between antigen presenting cells, T lymphocytes, and tumor cells to remove immunosuppressive signals. Here, we review their mechanism of action, efficacy, and indications, and then focus on the neurologic complications that occur in cancer patients undergoing ICI treatment.
Immune checkpoint inhibitors: mechanism, types, indications, and efficacy
Cancer growth and progression are characterized by immune suppression. ICIs work by releasing immunosuppressive signals that inhibit the antitumor immune response. In the normal state, immune checkpoints dampen the host immune response to protect normal tissues. Immune checkpoints keep T-cells inactive, prevent autoimmunity, and provide self-tolerance. Cancer cells take advantage of these checkpoints. By activating checkpoint molecules, cancers suppress T-cell activity and evade the antitumor immune response. ICIs are monoclonal antibodies that block checkpoint signals and reinvigorate the host immune responses to allow T-cells to infiltrate the tumor and improve outcomes.
Three categories of immune checkpoint inhibitors received initial approval from the Food and Drug Administration, including programmed cell death 1 (PD-1) inhibitors, programmed cell death ligand 1 (PD-L1) inhibitors, and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) inhibitors ( Table 29.1 ). Agents within each of these categories inhibit this substrate and prevent signaling at the immune checkpoint, allowing activated T-cells to infiltrate the tumor.
| Checkpoint inhibitor | Type | Approved indications |
|---|---|---|
| Pembrolizumab | PD-1 inhibitor | Melanoma, NSCLC, classic Hodgkin lymphoma, SCC of head and neck, urothelial carcinoma, gastric cancer, solid tumors with high micro-satellite instability or mismatch-repair deficiency |
| Nivolumab | PD-1 inhibitor | Melanoma, NSCLC, classic Hodgkin lymphoma, SCC of head and neck, urothelial carcinoma, RCC, colorectal carcinoma with high micro-satellite instability or mismatch-repair deficiency |
| Atezolizumab | PD-L1 inhibitor | Urothelial carcinoma, NSCLC |
| Avelumab | PD-L1 inhibitor | Urothelial carcinoma, Merkel-cell carcinoma |
| Durvalumab | PD-L1 inhibitor | Urothelial carcinoma |
| Ipilimumab | CTLA-4 inhibitor | Melanoma |
PD-1 inhibitors include pembrolizumab and nivolumab. Both are approved for the treatment of melanoma, non–small-cell lung cancer (NSCLC), classic Hodgkin lymphoma, squamous cell cancer of the head and neck, and urothelial carcinoma. Nivolumab is also approved for treating renal cell carcinoma (RCC) and colorectal carcinoma with high micro-satellite instability or mismatch-repair deficiency. Pembrolizumab is also approved for gastric cancer and solid tumors with high micro-satellite instability or mismatch-repair deficiency. PD-L1 inhibitors bind to the PD-1 ligand and include atezolizumab, avelumab, and durvalumab. Each of these therapies is approved for urothelial carcinoma. Additionally, atezolizumab is also approved for treating NSCLC, and avelumab for Merkel-cell carcinoma. Ipilimumab is a CTLA-4 inhibitor. As a monotherapy, it is approved for melanoma. In addition, it is used in combination with other checkpoint inhibitors for treating melanoma and various other cancer types.
ICIs are highly effective in treating patients with these cancers. Objective responses occur in 40–45% of patients with melanoma who are treated with pembrolizumab or nivolumab as first-line treatment. For patients with relapsed NSCLC who have failed chemotherapy, up to 20% will respond to ICIs. For RCC, 25% of patients had radiographic response to nivolumab. This response is often enhanced by combination therapy. The median progression-free survival is up to 11.5 months with nivolumab plus ipilimumab, compared with 2.9 months with ipilimumab monotherapy and 6.9 months with nivolumab monotherapy.
Non-neurologic immune-related adverse events
Despite their efficacy, ICIs can contribute to significant morbidity and even mortality from autoimmune-related complications. These immune-related adverse events (IRAEs) are common and can affect any organ system, including rarely the brain. Common manifestations include gastrointestinal, dermatologic, hepatic, endocrine, and pulmonary toxicities. Colitis occurs in approximately 25% of patients treated with ipilimumab and less than 5% of patients treated with PD-1 or PD-L1 inhibitors. Pneumonitis occurs in 2–5% of patients treated with ICIs. In these cases, both colitis and pneumonitis can be life-threatening. Hypophysitis occurs in up to 10% of patients treated with CTLA-4 inhibitors, and rarely in other types of ICIs. Early recognition is paramount, as this can result in adrenal/hypothalamic crisis and death. Hypothyroidism occurs in up to 20% of patients treated with checkpoint inhibitors, with hyperthyroidism being far less common. One percent of patients prescribed PD-1 or PD-L1 inhibitors and 10% of patients prescribed CTLA-4 inhibitors will develop hepatitis. Skin manifestations are common and occur in up to 30% of patients treated with ICIs. Symptoms include pruritus, acneiform rash, and toxic epidermal necrolysis. Cardiac toxicity may also occur and commonly manifests as inflammatory myocarditis that is present in less than 1% of patients treated with ICIs.
Neurologic adverse events are rare. Although headache occurs in 3–12% of patients, serious neurologic events occur in only 1% of patients treated with ICIs. Despite their rarity, cases of neurologic adverse events with ICIs can be life-threatening, and thus a high index of suspicion is needed to identify these cases early and intervene appropriately. The following cases highlight the breadth and depth of neurologic adverse events and describe the evaluation and management decisions in these patients.
Clinical cases
Case. A man presents with rapid onset gait imbalance and bilateral lower extremity weakness 3 weeks following initiation of combination nivolumab and ipilimumab as first-line systemic therapy for metastatic melanoma. Following cycle two, his gait dysfunction worsens, and he has numerous falls. ICIs are discontinued, but his weakness and numbness progresses from walking independently to being wheelchair bound over a few months. Physical examination is notable for loss of proprioception and vibration sense in bilateral toes and ankles, positive Romberg, symmetrically absent Achilles and diminished plantar reflexes, and intact motor strength (5/5) except for the right lower extremity (4/5). After failure of outpatient treatment with an oral prednisone taper, he is hospitalized. Workup includes MRI Brain with nonspecific T2-hyperintense white matter lesions and lumbar puncture with a mononuclear leukocytosis and two well-defined gamma restriction bands not present in the serum with normal IgG index, but no malignancy, significant B-cell or blast population on flow cytometry, negative paraneoplastic panel, and negative cytomegalovirus (CMV). Electromyography/nerve conduction velocity (EMG/NCV) show widespread subacute, severe sensory greater than motor neuropathy, with primarily demyelinating and secondary axonal features. These findings are consistent with a Common Terminology Criteria for Adverse Events (CTCAE) grade 4 sensorimotor demyelinating polyneuropathy. Treatment with intravenous corticosteroids as well as a 5-day course of intravenous immunoglobulin (IVIG) is pursued with minimal response. Despite ongoing treatment with oral prednisone and physical therapy, he remained wheelchair bound and died 5 months following initiation of ICI treatment from complications of a urinary tract infection.
Teaching Points. This case highlights several features of neurologic complications of ICIs including (1) the potential for life-threatening complications and (2) the concern for severe IRAEs in patients on combination treatment with two ICIs. There is no standard or typical presentation of a neurologic adverse event of immune checkpoint inhibitors. A spectrum of syndromes can occur ranging from mild neurologic symptoms such as headache to severe and life-threatening manifestations including encephalitis, myelitis, aseptic meningitis, meningoradiculitis, Guillain-Barré–like syndrome, myasthenic syndrome, and peripheral neuropathy, such as this case. , Mortality may be as high as 18%, but with prompt diagnosis and treatment, 70–80% of patients recover. Of note, higher incidence of IRAEs requiring drug discontinuation has been observed in patients on combination ICI therapy as well as more severe complications with long-term effects. This has not been reliably demonstrated for patients with neurologic IRAEs but can be helpful to consider when evaluating a cancer patient with new neurologic symptoms undergoing ICI therapy. This is anticipated to be particularly relevant as more combination regimens are utilized.
Clinical Pearls
- 1.
Serious neurologic IRAEs have been shown to occur in up to 1% of patients receiving ICIs.
- 2.
In general, IRAEs have been shown to be more common and more severe in patients receiving combination therapy.
Case. A man with metastatic RCC presents with fever to 39.2°C and a transient speech disturbance. He had completed four cycles of combination ipilimumab and nivolumab given every 3 weeks and then five cycles of nivolumab monotherapy given every 2 weeks, with symptom onset occurring 3 days after the fifth dose of nivolumab. The following day, he develops fluctuating confusion and becomes somnolent. Initial laboratory tests are only notable for increased serum creatinine, but MRI Brain shows mild diffuse dural enhancement. Cerebrospinal fluid (CSF) analysis from lumbar puncture demonstrates mononuclear pleocytosis, increased protein, and normal glucose. He is initially treated with intravenous acyclovir, ceftriaxone, and ampicillin for possible infectious meningoencephalitis, but shows no improvement and CSF cultures, cryptococcal antigen, and polymerase chain reaction (PCR) for herpes simplex virus types 1 and 2, varicella zoster, CMV and Epstein-Barr viruses are all negative. CSF cytology is also negative for tumor cells. EEG shows diffuse non-specific slowing. As a result, an immune-related meningoencephalitis is suspected and treatment with high-dose prednisone is initiated. The patient shows significant clinical improvement and reaches full recovery.
Teaching Points. This case reveals the idiosyncratic onset of neurologic complications that is not dose-dependent and cannot be predicted by antecedent symptoms or red flag signs. The time to onset of neurologic IRAEs varies significantly and can occur at any point during treatment. The median time to onset of neurologic IRAE symptoms is 8 weeks following initiating ICI therapy. The median interval between the last dose of ICI and symptom onset is approximately 2 weeks. In these studies, however, there was a wide range in time of onset observed. In this case, symptoms began at 19 weeks after initiation of ICI therapy and 3 days after the last ICI dose.
Clinical Pearls
- 1.
Neurologic IRAEs from ICIs are idiosyncratic and can occur at any point during treatment.
- 2.
Neurologic IRAEs are highly variable and have been shown to occur throughout the nervous system, with presentations including encephalitis, meningitis, myelitis, meningoradiculitis, myasthenic syndrome, Guillain-Barré–like syndrome, and peripheral neuropathy.
Case. A man presents to the clinic with 1 week of low back pain, bilateral hand numbness, and progressive lower extremity weakness approximately 9 months after initiating combination nivolumab and ipilimumab as first-line systemic therapy for metastatic melanoma. He had completed four cycles of treatment prior to symptom onset. Physical examination is notable for bilateral lower extremity dysmetria, reduced sensation to light touch and pinprick with a sensory level to pinprick around the T8 dermatome on the back, and reduced to absent reflexes with full muscle strength, bulk, and range of motion throughout, creating a picture consistent with a thoracic myelopathy. As he is unable to safely ambulate without assistance, he is admitted to the hospital for further workup. An MRI of the brain is obtained and shows no acute pathology, and lumbar puncture is performed and demonstrates a mild mononuclear pleocytosis with no evidence of malignancy or infection. Somatosensory evoked potentials show prolonged P37 latency, consistent with myelopathy. Given a negative workup for infection and tumor progression, he is diagnosed with a CTCAE grade 4 transverse myelopathy secondary to nivolumab/ipilimumab therapy. His immunotherapy is discontinued, and he is treated with intravenous followed by oral corticosteroids. Symptoms improve significantly over the ensuing 4 weeks with only mild persistent lower extremity numbness.
Teaching Points. Neurologic IRAEs of ICIs are highly varied. Like in this case, when evaluating a patient who presents with a new neurologic syndrome and has been treated with these therapies, the general differential diagnosis must include: neurologic IRAE, central nervous system (CNS) infection, tumor progression, or a primary neurologic disease. As in many cases of drug toxicity, this is a diagnosis of exclusion, though if the concern is high, then that should not delay starting treatment, which is described in the following section. The initial workup will depend largely on the neurologic syndrome consistent with the presenting symptoms. The American Society of Clinical Oncology (ASCO) has published a clinical practice guideline regarding diagnosis and treatment of the most common and/or severe IRAEs, including neurologic toxicities. The toxicities they address include myasthenia gravis, Guillain-Barré syndrome, peripheral neuropathy, autonomic neuropathy, aseptic meningitis, encephalitis, and transverse myelitis. These recommendations can be reviewed in Table 29.2 .
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