American Thyroid Association 88th Annual Meeting:

Combination Immunotherapy to Treat Advanced Thyroid Cancers

With Timothy Chan, MD

 A growing number of new immunotherapy drugs, including checkpoint blockers, vaccines, and monoclonal antibodies, have demonstrated efficacy in treating some forms of advanced cancer—arresting growth, shrinking, and in some cases prolonging lives.1 To appreciate the depth of this research, combination therapies involving more than 240 immune-based therapeutics were being tested against a variety of cancers in 2017.2

While only a small percentage of patients with cancer have demonstrated a good response to these novel treatments, the focus of ongoing research has aimed to employ ever more targeted immunotherapy combinations to achieve a better response against all advanced forms of cancer, including in anaplastic thyroid cancers. 

Seeking Durable Therapies for Treatment-Resistant Cancers

The goal now is to determine who does and who doesn’t respond to immune checkpoint blockade and monoclonal antibody therapies, so we can refine these regimens to achieve  precise use of immunotherapy that is effective across all advanced cancers,” said Timothy Chan, MD, PhD, professor of medicine PaineWebber Chair in Cancer Genetics at Memorial Sloan Kettering Cancer Center and Cornell Medicine, in New York City,1 during  a keynote presentation on the challenges of delivering efficacious anti-tumor immune and immunity-based therapeutics for advanced thyroid cancer at the 2018 American Thyroid Association Annual Meeting in Washington, DC.

While gaps in the field remain, immune checkpoint inhibitors have advanced the durability of cancer treatment such that some individuals have demonstrated a good response, even as there have been many others for whom this hasn’t worked, especially for differentiated thyroid cancer.1

“The notion of hot and cold tumors are not mutually exclusive, rather cancers are more fluid, influenced by their surroundings and by their mutational load, which produces distinctive neoantigens on the cancer cell surfaces, and this is what must be considered in managing these patients,” Dr. Chan told EndocrineWeb.

Therapies targeting multiple aspects of a tumor cells’ ability to resist immunotherapy treatment represents another approach in the fight against cancer.  Combination therapies using tyrosine kinase inhibitors (TKI) are good examples, as these drugs are used to disrupt signaling pathways that are driven by protein tyrosine kinases that may help tumors avoid immune recognition, he said. As cancers develop and become more aggressive, the immune system has found ways to reject foreign entities but these pathways may be activated to help tumor cells evade immune-based killing.1

“The challenge arises because the therapeutic window is very narrow,” said Dr. Chan. “It isn’t about whether tumors do or don’t have specific driver mutations but how much non-self can be targeted, or recognized so malignancies for which immunotherapeutic agents will work and prove durable.”1

And, this is just the beginning,1 he said. "There have been several failed phase 3 trials, which suggests the need for a more focused approach to testing if we are going to be able to help the greater majority of cancer patients who still need an effective treatment."

“The more important takeaway is that we have been able to learn from each negative study. As the findings are never homogeneous, they offer enormous insights from which we can learn. Moreover, the timing of treatment appears important. For example, treating stage 3 non-small cell lung cancer with chemotherapy for six months followed by anti-PD1 inhibition has shown such exceptional promise that it has become the standard of care,” Dr. Chan told EndocrineWeb

Pursuing Precision Medicine to Individualize Cancer Therapy

Investigators are looking to better understand why certain patients and some cancer types are more sensitive to immunotherapy.  Mutational load is one feature that is being examined,1 said Dr. Chan. 

“This is a continuous variable, with a dose-response.  Many tumors follow this rule but others don’t, which suggests that we don’t know the mechanism of action fully,” he said. An individual patient’s microenvironment can promote or reject treatment, which is influenced by several factors. See Table 1

Factors indicating which patients will benefit from precision cancer therapies.

Immunity may be analyzed with large-scale technologies: Tools to predict antigens in tumor cells and tools to predict T-cell receptors (TCR) in CD4+ or CD8+ T cells.3 Combination therapy using anti-PD1 staining has been approved and provides a rough measure of expression level: under 1%; between 1-49%; more than 50%, which are levels some have used to predict response to anti-PD1 agents. While PD1 can enrich for responders, providing validation of immunotherapeutic effect, it is a useful tool but not perfect, Dr. Chan said.

Also, in the tumor microenvironment, tumor-associated macrophages (TAM) are present at every stage of cancer progression and demonstrate an adaptive characteristic in which they can both stimulate tumor cell invasion—promoting growth and fostering metastasis—and also exert immunosuppression, making them potential targets for combination therapy provided the right contexts can be identified.1

How do we improve TMB? For which cancers? The following is a list of considerations to be addressed in improving precision immunotherapeutic decision-making:1

  • Whole exome sequencing versus targeted panel
  • Total number of exotic mutations versus Mb mutations
  • What is the threshold for # of mutations
  • What types of mutations to count
  • Neoantigen quantity
  • Clonality—This affects immunotherapy outcomes;  clonal neoantigens tend to be more immunogenic, and strongest neoantigens are highly clonal mutagens.4

Efficacy of Combination Therapy for Anaplastic Thyroid Cancer

For advanced thyroid cancers, particularly anaplastic thyroid cancers (ATC), the responsiveness to immune checkpoint blockage agents has been poor, to date. “However, we know that mutations and neoantigen burden predict response in general4,5 said Dr. Chan.  

In other tumor types, “high mutation burden patients did much better while patients with a low burden did worse,6 begging the question: Given that ATCs have plenty of mutations, what needs to be targeted to enable T cells to recognize and kill ATC cells? he said.

“Thyroid cancer makes up a group of tumors that favor recruitment of suppressor macrophages. Therefore, employing certain tyrosine kinase inhibitors—which can target macrophages as well as angiogenesis—with immune checkpoint blockade may achieve a better response,” he said.

With regard to autoimmune thyroiditis, the usual IPCR rate is 1-2% versus up to 20% with treatment of immune checkpoint ihibition.1

What is underlying this? “It is in part a question of what the immune system sees as foreign and subsets of peptides that are recognized. Neoantigen peptides that undergo mutations are recognized by the immune system as foreign, causing T cells to respond,1 according to Dr. Chan.

Autoimmunity in the thyroid as a side effect of immunotherapy may be related to cross-reactivity of thyroid cells with cancer-related antigens or may be a result of the elimination of immune checkpoints needed to keep peripheral tolerance in check.1

Cancer Therapeutics: What Might Be Expected in the Near Term 

The next step may be to consider: How do tumor cells recognize cancer cells? What is the role of mutagens, transcription on peptides presented or expressed? Tumor responsive will depend on many genetic determinants, which can be used to assess any benefit derived from anti-CTLA4 or anti-PDI treatment and to identify new targets.1

Ultimately, the amount of foreignness in tumors and the interplay of factors and interconnectedness of markers is essential to understand in order to better anticipate who will respond and with which treatment, and this also will depend on feasibility and robustness of targeted therapeutics,1 said Dr. Chan.

“We’ve learned a lot about why patient responses vary across different types of cancer. For thyroid cancer, it seems that the ability of immune cells to attack thyroid cancer is blunted by a number of factors, such as low mutation rates and the inability of T-cells and immune cells to actually get into the tumor and kill thyroid cancer cells,” said Dr. Chan.

Very aggressive thyroid cancers like anaplastic thyroid carcinoma (ATC) appear to be protected by factors including macrophages which may even prevent T-cells from killing tumor cells. Therefore, these are barriers that have to be overcome as researchers attempt to translate immunotherapy to the thyroid cancer population so patients can benefit.1

“This may be achieved in a variety of ways but given what we have learned about thyroid cancer from both the genomics and immunology perspective, it is likely to require more than just the current approaches with a single therapy such as anti-PD1,” Dr. Chan said. The response rates have been low, essentially in the single digits. This poor response is likely due to a combination of a suppressive tumor microenvironment environment and the mutational profiles of thyroid cancers.

Theoretically, thyroid cancers should have enough mutations to be rejected if the immune surveillance can be affected in the right way, or in a strong enough manner. Investigators have been trying to do exactly that, employing a combination of two different types of immunotherapies.

“There are very exciting approaches under trial using combination therapies like anti-VEGF agents, TKIs, and other immune checkpoint inhibitors that appear to boost the immunologic effect in thyroid cancers,” he said. “And finally, there is a new generation of vaccine trials that are being developed to specifically boost the immune response to individual antigens. These may potentially have effects against tumors with low mutations by generating an immune response targeted to those specific mutations.”

Combination therapies such as anti-VEGF, TKI, and immune checkpoint inhibitors offer exciting possibilities currently under investigation.1

“We can say that cancer treatment is moving toward a more personalized approach and this should result in exciting dividends for patients with thyroid cancer,” said. Dr. Chan.

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