Empowering our immune system in the fight against cancer

Cancer is a complex, multifaceted group of diseases that arguably represent the greatest challenge faced by biomedical researchers in the developed world. Conventional treatments typically combine surgery with radiation or chemotherapy to stop the rampant spread of tumour cells. Unfortunately, these traditional treatments are equally potent against healthy cells and result in collateral damage within the patient’s body. For this reason, targeted immunotherapies in the form of monoclonal antibodies – which have the intrinsic potential to selectively target tumour cells – have recently reached the forefront of cancer research.

The history of monoclonal antibody therapy

At the turn of the 20th century in Berlin, German scientist Emil von Behring discovered that he could protect a guinea pig from diphtheria with an injection of serum from another that had recovered from the disease. This first discovery of an “anti-serum” at work won von Behring the first Nobel Prize in Physiology or Medicine in 1901. Following these observations, his colleague, Paul Ehrlich, hypothesized that within the serum were substances that could selectively neutralize different toxins or cancer cells, which he fancifully termed “Magische Kugel” or “Magic Bullets”.

Rituximab Fab in complex with CD20 epitope peptide (grey).
Rituximab Fab in complex with CD20 epitope peptide (grey).

As research progressed, these “Magic Bullets” became recognizable as antibodies, molecules with clonal specificity and the potential to recognize billions of different targets. In the 1970s, immunologists Cesar Milstein and George Kohler serendipitously launched a biomedical revolution with their engineering of lab-made monoclonal antibodies (mAbs) from hybridoma cultures of murine B cells fused to myelomas. These mAbs possessed a single specificity and could be produced in large quantities from immortalized cultures. Their potential as tools in the fight against cancer would soon be recognized.

In 1979, cancer biologist Lee Nadler and immunologist Phil Stashenko collaborated to create the first mAb specific to a type of cancer cell – an antibody that recognizes CD20 on the surface of non-Hodgkin lymphoma B cells. When they administered this first mAb to a patient suffering from advanced lymphoma, they regrettably discovered that the immunotherapy actually worsened his condition. Unfortunately, the mAb treatment did not trigger a strong anti-cancer response, owing in part to the fact that these mouse-derived antibodies were actually targeted by the patient’s own immune system. Nevertheless, these seminal experiments paved the way for other approaches, including the development of recombinant chimeric antibodies that fused mice variable regions with human constant regions to avoid immune rejection. Finally, in 1997, Rituximab, a chimeric anti-CD20 mAb developed by Biogen/Genentech passed clinical trials and was approved for the pharmaceutical market as a non-Hodgkin lymphoma immunotherapy.

Enhancing the immune response against cancer
mAb immunotherapies function by specifically targeting tumour cells that overexpress a certain kind of cancer-specific antigen. Although many of these antigens, such as Rituximab’s target CD20, are found on healthy cells, cancer cells often aberrantly display these markers at a much higher level on their cell surface. Binding of these mAbs to tumour cells can induce their death through several different mechanisms – receptor blockade, induction of apoptosis, or antibody-dependent cellular cytotoxicity. The majority of approved therapeutic mAbs for cancer are of the IgG1 class, designed to preferentially engage stimulatory Fcg receptors on NK cells, macrophages, and granulocytes. Cross-linking of these stimulatory receptors can induce killing or phagocytosis of these mAb-targeted cells by various immune cells.

The clinical advantage of developing mAb therapies
As of late 2013, there were 13 FDA-approved mAbs for cancer treatment on the US pharmaceutical market. For a medical biotechnology that exploded onto the scene almost 20 years ago in 1997, on the surface this is a wholly underwhelming number. However, when healthcare is in question, quality trumps quantity. Of the hundreds of mAbs that are touted as the next “magic bullet”, very few actually make it into the pipeline. Even those that do must continuously pass clinical efficacy tests or face withdrawal. Characterization of any therapeutic mAb requires rigorous examination to understanding how they function in the human body. These mAbs must undergo specificity analysis for their tumour targets in vitro followed by detailed studies of distribution and effectiveness in animal models of cancer.
The most promising candidates reach the clinical evaluation phase. At this stage, the therapeutic mAb is radiolabelled, injected and tracked within cancer patients to measure levels of mAb deposited in the tumour relative to healthy tissue. This information can prove crucial for predicting side effects of the mAb, as well as for strategic planning of dosage and scheduling. Finally, in order to attain the FDA seal of approval, these mAbs must prove, in clinical trials, to be significantly more effective versus established therapeutics with respect to patient survival.

Perhaps the most attractive characteristic of mAbs when compared to conventional radiation or chemotherapy is their innate specificity – usually resulting in substantially milder side effects on patients. Unfortunately, there are instances where therapeutic mAbs are specific enough to recognize malignant cells but the ensuing immune response is not potent enough to prevent metastasis.

Antibody-drug conjugates: greater than the sum of their parts?
In response, researchers have developed the antibody-drug conjugate (ADC). This relatively new class of targeted therapy combines the raw potency of chemotherapeutic agents or radiation therapy with the specificity of the mAb. ADCs are comprised of an antibody (or fragment) chemically linked to an active drug. These ADCs have incredible potential when compared with naked mAbs or chemotherapeutic administration alone as they can deliver a much higher concentration of the conjugated drug directly to the cells bearing cancer antigens, while retaining the biological functions of the antibodies themselves. A mAb-bound cancer cell will uptake the ADC, leading to intracellular linker cleavage, release of the cytotoxic cargo and induction of cell death. Unsurprisingly, intricate bioengineering between the mAb, linker, and cytotoxic drug is pivotal for development of a successful ADC.

[pullquote]Invented as a laboratory tool for evaluating the basic understanding of antibody diversification, the impact that monoclonal antibodies have had on cancer therapy has been nothing short of remarkable.[/pullquote]

The first approved ADC was Pfizer’s Mylotarg, an acute myeloid leukemia therapy comprised of a mAb targeting myeloid antigen CD33 conjugated to a DNA-damage inducing agent. After FDA approval under an accelerated program in 2000, Mylotarg achieved initial success before a 2004 follow-up study revealed dangerous side-effects of the drug that were overlooked during clinical trials. Within the paper were results that showed Mylotarg treatment leading to no significant improvement in patient survival and an increased risk of death due to veno-occlusive disease, a liver complication that arises when high-dose chemotherapy is applied prior to bone marrow transplantation, a common procedure for cancer patients undergoing radiation therapy. Further studies showed that the mAb and drug segments of the ADC were dissociating prematurely from each other, leading to dangerous levels of the cytotoxic agent interacting with healthy cells. Mylotarg’s celebrity as the first ADC on the market came to an infamous close in 2010 when it was withdrawn by Pfizer.

This dark chapter in mAb therapy prompted scientists to re-evaluate the technique of linking mAb and cytotoxin together. Researchers are currently exploring methods to refine the linker technology to achieve a balance between stability during circulation of the ADC and efficient release upon internalization into cancer cells. Today, two ADCs are available on the market: Adcetris, a CD30 mAb for the treatment of Hodgkin lymphoma, and Kadcyla, the anti-HER2 (Herceptin) mAb for a subtype of breast cancer. Both of these two ADCs are conjugated to powerful inhibitors of microtubule assembly – DM1 and MMAE – drugs that are deemed too dangerous for free administration. Both Adcetris and Kadcyla were approved by Health Canada in 2013.

Novel strategies for mAb immunotherapy
In addition to ADCs, cancer researchers are developing new approaches to tackle cancer from unique angles with mAb technology. As an example, instead of binding overexpressed antigens to help kill cancer cells, some mAbs have been designed to help the patient’s own immune system overcome the immunosuppressive environment that is a hallmark of many tumours. One of these mAbs, Ipilimumab, has been approved for melanoma treatment and functions by binding to and blocking the activity of CTLA4 on T cells. CTLA4 is an inhibitory receptor that curtails T cell activation; Ipilimumab unleashes these T cells from suppression with the goal of amplifying the cytotoxic anti-tumour response. Other immunomodulatory mAbs that target negative regulators of T cell activation such as PD-1 may have an even greater clinical impact, as shown in ongoing clinical trials.

Even more extraordinary are bispecific mAbs designed to possess two antigen specificities on one molecule. For instance, one such mAb in phase II clinical trials, Blinatumomab, combines binding sites for both B cell CD19 and T cell CD3, recruiting and facilitating cytotoxic T cell engagement – regardless of specificity – to their non-Hodgkin B cell lymphoma targets.

Conclusions
Invented as a laboratory tool for evaluating the basic understanding of antibody diversification, the impact that mAbs have had on cancer therapy has been nothing short of remarkable. Their efficacy, specificity, and relative safety ensure that the latest mAb immunotherapies will continue to be instrumental in the fight against cancer.

 

 

References
Bargou, Ralf, et al. “Tumor Regression in Cancer Patients by Very Low Doses of a T Cell–Engaging Antibody.” Science 321 (2008): 974-977. Print.

Cohen, Adam D. et al. “Gemtuzumab ozogamicin (Mylotarg) Monotherapy for Relapsed AML after Hematopoietic Stem Cell Transplant: Efficacy and Incidence of Hepatic Veno-occlusive Disease.” Bone Marrow Transplantation 30 (2002): 23-28. Print.

De Lartigue, Jane. “Antibody-Drug Conjugates Target Drug Delivery.” Targeted Oncology (2013): 1-6. Web. 20 Jan 2014. < http://www.targetedonc.com/publications/targeted-therapies-cancer/2012/november-2012/antibody-drug-conjugates-target-drug-delivery/1>

Fournier P., and Volker Schirrmacher. “Bispecific Antibodies and Trispecific Immunocytokines for Targeting the Immune System Against Cancer: Preparing for the Future.” BioDrugs 27 (2013): 35-53. Print.

Harrison, Chuck. “Magic Bullets: The Next Evolution in Targeted Cancer Therapy.” Charles River Eureka. 16 Oct 2012. Weblog. 15 Jan 2014. < http://www.criver.com/about-us/eureka/blog/october-2012/magic-bullets>

Hodi, F. Stephen. “Improved Survival with Ipilimumab in Patients with Metastatic Melanoma.” The New England Journal of Medicine 363 (2010): 711-723. Print.

Jefferson, Erica. “FDA: Pfizer Voluntarily Withdraws Cancer Treatment Mylotarg from U.S. Market. FDA News Release. 21 Jun 2010. Web. 30 Jan 2014. <http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm216448.htm>

Larson, Richard A, et al. “Final Report of the Efficacy and Safety of Gemtuzumab Ozogamicin (Mylotarg) in Patients with CD33-Positive Acute Myeloid Leukemia in First Recurrence.” Cancer 104 (2005): 1442-1452. Print.

Pagnotta, Laura. “Health Canada Approves KADCYLA™ (trastuzumab emtansine) for the Treatment of HER2-positive Metastatic Breast Cancer.” Roche Canada. 12 Sep 2013. Web. 25 Jan 2014. <http://www.newswire.ca/en/story/1223743/health-canada-approves-kadcylatm-trastuzumab-emtansine-for-the-treatment-of-her2-positive-metastatic-breast-cancer>

Patlak, Margie. “Magic Bullets and Monoclonals: An Antibody Tale.” FASEB: Breakthroughs in Bioscience (2009). Print.

Sassoon, Ingrid, and Veronique Blanc. “Antibody-Drug Conjugate (ADC) Clinical Pipeline: A Review.” Methods in Molecular Biology 1045 (2013): 1-27. Print.

Scott, Andrew M., Jedd D. Wolchok, and Lloyd J. Old. “Antibody Therapy of Cancer” Nature Reviews Cancer 12 (2012): 278-287. Print.

Shaughnessy, Allen F. “Monoclonal Antibodies: Magic Bullets with a Hefty Price Tag.” BMJ 345 (2012): 1-3. Web. 20 Jan 2014. < http://www.bmj.com/content/345/bmj.e8346>

Sievers, Eric L., and Peter D. Senter. “Antibody-Drug Conjugates in Cancer Therapy.” Annual Review of Medicine 64 (2013): 15-29. Print.

Sliwkowski, Mark X., and Ira Mellman. “Antibody Therapeutics in Cancer.” Science 341 (6151) (2013): 1192-1198. Print.

Sullivan, Meghan, et al. “Harnessing the Immune System’s Arsenal: Producing Human Monoclonal Antibodies for Therapeutics and Investigating Immune Responses.” F1000 Reports Biology 3 (2011): 1-8. Web. 29 Jan 2014. < http://f1000.com/prime/reports/b/3/17/pdf>

Topalian, Susan L., et al. “Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer.” The New England Journal of Medicine 366 (2012): 2443-2454. Print.

Weiner, Louise M., Joseph C. Murray, and Casey W. Shuptrine. “Antibody-Based Immunotherapy of Cancer.” Cell 148(6) (2012): 1081-1084. Print.

Wolchok Jedd D., et al. “Nivolumab plus Ipilimumab in Advanced Melanoma.” The New England Journal of Medicine 369 (2013): 122-133. Print.

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Michael Le

Managing Editor
Michael is a 4th year PhD student in the Department of Immunology at the University of Toronto studying how B cells diversify their antibodies to fight infections. He enjoys staying active, playing board games, and supporting his beloved Arsenal FC.

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