Author Archives: Dylan Buskermolen

Immunotherapies – What’s all the Buzz About?

https://kids.frontiersin.org/article/10.3389/frym.2017.00040

The latest buzz in cancer research is talk of immunotherapies. The basis of immunotherapies is to empower the patient’s own immune system to mount an “attack” against cancer. This seems like a very enticing idea as it takes advantage of a natural process and avoids the classic cutting, burning and zapping of traditional cancer treatments.

Immunotherapies themselves encompass a wide range of treatment strategies. Vaccines can be used to stimulate immune cells to target foreign proteins found on cancer cells or viruses that are known to cause cancers. This type of strategy is currently used in preventative cancer vaccines against Human Papilloma Virus (HPV). HPV is the cause of virtually all cervical cancers, among others, and this vaccine is very effective at reducing the incidence of these cancers1.

Another type of immunotherapy is called adoptive cellular therapy, which involves taking immune cells, called T-cells, from the patient’s tumour, stimulating them to grow and divide, and re-injecting them into the patient. This method has been effective at treating patients with metastatic melanoma, illustrated by 50% response rates and a one-year survival rate of 60%. Such results are previously unheard of in this disease2. Technological advances have allowed researchers to modify these T-cells while they are out of the body so that they target a cancer-specific protein. These so-called chimeric antigen receptor T-cells (CAR T-cells) are a very hot topic in cancer immunotherapy at the moment and are being tested clinically for various blood cancers such as leukemia3.

Another heavy hitter in the ring of immunotherapies is immune checkpoint blockade (ICB). T-cells have natural mechanisms to dampen their own activity, ultimately to prevent autoimmunity. This involves a receptor on the T-cells (e.g. PD-1, CTLA-4) binding to its partner, which is expressed on other immune cells. Cancers often co-op this method by expressing the binding partner themselves, which turns off the T-cells and prevents anti-cancer activity. Then, the goal of ICB is to use antibodies to block these checkpoint proteins on T-cells from binding their partners. This keeps the T-cells “on” and ready to attack cancer cells. ICB has been dramatically effective in melanoma, as well as some lung and kidney cancers4–6.

Both adoptive cellular therapy and ICB have been approved by the FDA for various cancers and clinical indications. ICB antibodies such as nivolumab and ipilimumab have been approved for front-line treatment of metastatic melanoma7. Other cancers are playing catch-up, and most approvals to-date are for the use of immunotherapies only after a patient has failed at least two other treatment types. The hesitancy for full approval stems from a lack of efficacy in all patients.

A crucial next step is to investigate why some patients do respond while others don’t. There are many possible biological and immunological reasons why only some patients respond8, but the goal remains to develop a simple test that could be performed in clinic to predict response. Once this sort of test is validated, it will become faster and easier to approve and fund immunotherapies for patient subsets that are likely to respond.

Ongoing research into cancer immunotherapies is occurring at Queen’s University in the Division of Cancer Biology and Genetics of the Queen’s Cancer Research Institute. While some research focuses on developing tests to predict response to immunotherapies, other research focuses on making patients more responsive to treatment. Our hope is that we can harness the power of the immune system in as many cancer patients as possible.

References:

  1. Vonka, V. & Hamsíková, E. Vaccines against human papillomaviruses–a major breakthrough in cancer prevention. Cent. Eur. J. Public Health 15, 131-9 (2007).
  2. Rosenberg, S. A. et al. Durable Complete Responses in Heavily Pretreated Patients with Metastatic Melanoma Using T-Cell Transfer Immunotherapy. Clin. Cancer Res. 17, 4550-4557 (2011).
  3. Park, J. H. et al. Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia. N. Engl. J. Med. 378, 449-459 (2018).
  4. Robert, C. et al. Nivolumab in Previously Untreated Melanoma without BRAF Mutation. N. Engl. J. Med. 372, 320-330 (2015).
  5. Lynch, T. J. et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J. Clin. Oncol. 30, 2046-54 (2012).
  6. Yang, J. C. et al. Ipilimumab (Anti-CTLA4 Antibody) Causes Regression of Metastatic Renal Cell Cancer Associated With Enteritis and Hypophysitis. J. Immunother. 30, 825-830 (2007).
  7. Drugs Approved for Melanoma. National Cancer Institute (2018). Available at: https://www.cancer.gov/about-cancer/treatment/drugs/melanoma. (Accessed: 10th December 2018)
  8. Sharma, P., Hu-Lieskovan, S., Wargo, J. A. & Ribas, A. Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell 168, 707-723 (2017).

This article was written by Alison Moore, an M.Sc. Candidate in the Department of Pathology and Molecular Medicine, and part of the Cancer Research Institute at Queen’s University.