Immune Checkpoint Inhibitors Can Induce Thyroid Dysfunction

A meta-analysis of 38 published studies, covering 7551 cancer patients, found an overall incidence of hypothyroidism of 6.6% and hyperthyroidism of 2.9%

With Zoe Quandt MD and Anupam Kotwal MD

Unfortunately, the cancer treatment can bring about thyroid complications.

Immune checkpoints are novel targets in the fight against cancer, but manipulating the immune system can have unintended consequences that need to be weighed against the potential benefits. In a recent ENDO2020 abstract, presenting author Zoe Quandt MD highlights some of the thyroid-related consequences of targeting immune checkpoints.

Immune Checkpoint Inhibitors (ICIs)

Immune checkpoints are inhibitory pathways designed to limit the immune response, essentially maintaining tolerance for “self” and preventing autoimmunity. They are initiated by receptor-ligand interactions between T-cells and other immune or tissue cells. Immune Checkpoint Inhibitors (ICIs), then, are a class of cancer treatment drugs that silence these checkpoints to allow an uninhibited T-cell response against solid tumors. There are currently three therapeutic ICI targets: the cytotoxic T-lymphocyte-associated antigen (CTLA4), the programmed cell death protein 1 (PD1), and the programed cell death ligand 1 (PD-L1).

CTLA4 is a surface receptor on activated T-cells. It binds CD80 and CD86 on antigen presenting cells. The interaction between CTLA4 and these ligands reduces the amplitude of the T-cell response. CD28 is the proinflammatory counterpart to CTLA4. When it binds to CD80 and CD86, an escalation of T-cell activity occurs.

PD1 and its associated ligand PD-L1 are both targets of ICI therapies. The PD1 receptor is expressed on T-cells and when it binds its associated ligand, PD-L1, it prevents the activation of the T-cells. Non-cancerous cells express PD-L1, but tumor cells typically express higher levels of PD-L1, granting them a type of immunoprotected status.

ICI Drug

Immune Checkpoint Target

Ipilimumab

CTLA4

Nivolumab

PD1

Pembrolizumab

PD1

Atezolizumab

PD-L1

Avelumab

PD-L1

Durvalumab

PD-L1

Table 1. FDA approved ICI and their associated immune checkpoint target.

Immune Checkpoint Inhibitor (ICI) therapy

One therapeutic strategy of ICI is to block CTLA4 before it can interact with its ligands, CD80 and CD68, leaving them free to interact with CD28 and unleashing the full strength of T-cell immunoactivity. Currently there is only one FDA approved ICI that targets the CTLA4 receptors (Table 1). The other strategy is designed to block either PD1 or PD-L1. This blocks the inhibitory pathway that keeps T-cells in a quiescent state and allows them to activate. There are several FDA approved anti-PD1 and anti-PD-L1 therapies (Table 1).

Therapies that block the immune checkpoints have been used on many solid tumor cancers, including breast, bladder, liver, lung, cervical and colon, but most commonly they have been used to treat melanomas. However, not all cancers are equally responsive. A review by Angulo et al. has shown that renal cancer patients treated with ICI monotherapies or treated with combination ICI therapies have gained significant survival benefit. On the other hand, a meta-analysis by Brahm et al. looking at brain cancers have suggested that neither glioblastomas nor brain metastases benefit from mono or combo therapies.

Monotherapy ICI treatment is simply using a single drug, most commonly Ipilimumab or Nivolumab, but several studies have used combination therapies, combining two ICI drugs or a single ICI drug with the current standard. When combining two ICI drugs, PD1 inhibitors (ie. Nivolumab) are usually paired with the CTLA4 inhibitor (Ipilimumab) to promote T-cell activation and increase the amplitude of T-cell response. PD1 inhibitors have also been combined with a PD-L1 inhibitor which promotes T-cell activation and removes tumor’s defense against T-cell activation.

As hopeful as this class of drugs is in the fight against cancer, immune checkpoints are normal and necessary components of the immune response. When checkpoints' pathways are silenced, collateral damage by unregulated T-cell activity can and does occur, causing immune-related adverse events (irAEs).

Immune-related adverse events can involve thyroid dysfunction

A recent ENDO2020 abstract by presenting author, Zoe Quandt MD, a clinical fellow in endocrinology and diabetes at the University of California in San Francisco, analyzed retrospective data from medical health records to determine how prevalent thyroid dysfunction is among ICI treated patients.

Records from 1146 cancer patients receiving ICI treatment who had no previous record of thyroid dysfunction were identified. Most cancers were melanomas and non-small cell lung cancer, with some renal cell cancer, glioblastomas, and other non-identified cancers. Anti-PD1 monotherapy was the most prevalent treatment with 45% of patients given pembrolizumab and 20% given nivolumab. Therapies targeting PD-L1 and CTLA4 were less prevalent as were combination ipilimumab/nivolumab therapy, each containing less than 10% of the study population.

Overall, 19% of patients developed irAEs involving the thyroid. Patients given combination therapy had a significantly higher rate of thyroid irAEs (31%) compared to those on monotherapies pembrolizumab and nivolumab both with 18%, and ipilimumab with 15% of patients.

These results confirm previous studies which also found significant increases in the number of thyroid irAEs among patients on combination ICI therapies. Ornestein et al. found that combination ipilimumab and nivolumab doubled the number of hypothyroid cases in cancer patients. They did not report on hyperthyroid cases. A more recent study by Barroso-Sousa et al. differentiated between hypo and hyperthyroid irAEs. The meta-analysis of 38 published studies, covering 7551 cancer patients, found an overall incidence of hypothyroidism of 6.6% and hyperthyroidism of 2.9%. Both types of thyroid disorders increased when patients were put on combination therapies,13.2% for hypothyroidism and 8.0% for hyperthyroidism.

How concerned should cancer patients be over thyroid related irAEs?

In light of a cancer crisis, what is the appropriate concern for developing thyroid-related irAEs? We turned to Dr. Quandt to find out. She told EndocrineWeb the following:

“For some people that have mild thyroid abnormalities, they can return to normal untreated. For those who need thyroid treatment to return to an euthyroid state, the dysfunction appears to be a permanent condition. Overall, the most important thing is for thyroid irAEs to be diagnosed quickly so that the right medications can be initiated if needed. If they don't get started, patients can have complications.”

In fact, thyroid related irAE’s might even be an indicator of improved survival in ICI treated cancer patients. Anupam Kotwal MD, assistant professor of endocrinology at the University of Nebraska Medical Center, told EndocrineWeb of a recent study he participated in with the Mayo Clinic in Rochester MN. In this retrospective study, ICI treated cancer patients who developed thyroid irAE’s had a longer survival and a lower mortality rate than those who did not. Furthermore, they attributed it to the PD-L1 ICI therapy.

How concerned should current thyroid patients be over ICI treatments?

While the studies mentioned thus far have focused on cancer patients with no prior diagnosis of hypo or hyperthyroidism, Dr. Kotwal addressed this question for us. He suggested “monitoring of thyroid hormone status (TSH and free T4) before starting any ICI. If laboratory data show hypothyroidism, then thyroid hormone replacement should be initiated. If the patient has known autoimmune hypothyroidism and is taking levothyroxine before initiation ICI, thyroid hormone status should be assessed, and they should be counseled on the possibility of dose adjustment following ICI therapy.”

The bottom line is that an awareness and early detection of thyroid irAEs by a patient’s cancer team is key, especially for those treating patients on combination ICI treatment. However, thyroid disorders, either prior to or as a result of ICI treatment, do not have to put a stop to treatment. A mindful eye on thyroid function should be a standard protocol when using ICI treatments.

There are no currently reported conflicts with regard to discussing this study by any author. 

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