Neurologic complications of immune checkpoint inhibitors

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.

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.