Marshalling Chemotherapy, Radiotherapy and the Immune System to Fight Cancer

A friendly doctor holding a patient's hand sitting at her desk for encouragement, empathy and support following a medical examination.
A friendly doctor holding a patient's hand sitting at her desk for encouragement, empathy and support following a medical examination.

Humanity’s war against cancer is a seemingly never-ending series of offensives and counter-offensives between two extremely tenacious opponents. We treated one cancer with radiotherapy and caused another in the process. [1] We discovered chemotherapy and cancer developed resistance. [2] We blocked the checkpoints that cancers use to evade the immune system only to find that many cancers reside in an immunologically “cold environment”. [3] Most recently we learned how to program immune cells to “see” targets on certain types of cancer, but production costs of these highly targeted-weapons limit how frequently they can be deployed. [4]

This is of course a linear oversimplification of the evolution of cancer therapy, but to avoid immediately being overwhelmed by the complexity of modern cancer medicine, I will focus on two key expansions of the war metaphor. The first is that each innovation has undergone successive waves of innovation, such that they are becoming ever more effective against cancer. The second is that we are combining treatments in ever more effective combinations to overwhelm cancer in the process.

Waves of attack

Three years after Roentgen discovered X-rays in 1896, radiation was already beginning to be used to treat cancer. Initially, radiotherapy was limited to the use of radium and low-voltage diagnostic machines to deliver the treatment to relatively broad areas. Unfortunately, these attacks failed to penetrate internal tissues in the case of deep-seated neoplasms.[1]

Since then, advances in physics and computer technology have vastly improved the methods, means and overall safety of cancer treatments. Discovering new types of radiation and harnessing higher-energy accelerators has allowed for the delivery of more intense doses of radiation to targeted areas while sparing healthy tissue. Cancer treatment progress includes the development of conformational radiation therapy (CRT) and conformational proton beam radiation therapy, which precisely map the location of cancer in three dimensions and use radiation or proton beams to attack the tumor from all directions. Intensity-modulated radiotherapy (IMRT) is similar to CRT, but the strength of the multi-directional photon beams can also be adjusted to deliver a higher dose to the cancer and spare normal surrounding tissue.[1]

It was recently discovered that small molecules are useful in delivering targeted, tumor-specific therapy, especially in men with metastatic castrate-resistant prostate cancer (mCRPC). PSMA-617 is a small molecule-targeting ligand that selectively targets prostate-specific membrane antigen (PSMA), which is commonly expressed on prostate cancer cells. It can be attached to lutetium-177, a radioactive vehicle.  177Lu-PSMA-617 has shown encouraging response rates in men who would otherwise have been directed to palliative therapy due to disease progression. Few side effects are seen since the therapy is highly specific and healthy, normal cells are generally unaffected. [5]

Other weapons against cancer include chemotherapy, which was first discovered during World War II when researchers studying mustard gas discovered that a compound known as nitrogen mustard works against lymphoma. Since then, various other chemotherapy agents have been discovered and are effective against numerous cancer types. Most importantly, approaches have changed in order to improve the effectiveness and reduce associated side effects of chemotherapy for patients. New drugs, new combinations of drugs and new delivery techniques have all played an important role in this evolution. [6]

Most recently, immuno-oncology drugs known as checkpoint inhibitors were approved by the US Food and Drug Administration (FDA). These drugs enable the immune system to recognize and attack cancer cells and are commonly used together with chemotherapy. In some patients, checkpoint inhibitors provide long survival benefits and sometimes even a curative outcome. Unfortunately, this only applies to a few cancer types, like skin, lung, bladder or head and neck. Even in these immuno-oncology sensitive cancers, only about 20-25% of patients will respond to currently available immuno-oncology drugs.[7]

Seeking ways to extend the benefit of immuno-oncology drugs to most cancer patients is of particular research interest. In order to accomplish this goal, it is important to point out that the immune system is made up of two components: innate immunity and adaptive immunity. Innate immunity is a non-specific defense system that the body activates to fight against any disease. Adaptive immunity is specifically activated based on the type of disease the body is facing. [8] To date, immuno-oncology agents have only activated the adaptive arm of the immune system. Recently, pre-clinical studies of a new class of immuno-oncology drugs has been shown to activate both the innate and adaptive immune systems in mouse models and human cells.[9]

Combining forces

Similarly to the adaptations seen with advancements in chemotherapy, the overall treatment strategy against cancer has changed over time. Combination therapy or using two or more drugs to achieve greater efficacy or similar efficacy with lower doses or lower toxicity has gained popularity as an approach to fighting cancer.[10]

The introduction of immuno-oncology agents has led to extensive testing of combination therapies as well as genetic sequencing to determine if specific treatments result in better outcomes based on patients’ clinical profiles. For instance, certain therapies are more efficient in patients who have previously been [or who are being] exposed to particular chemotherapies versus patients who are chemotherapy-naïve. Other chemotherapies have been found to have a synergistic effect and work better when given together than separately. While chemotherapy is often paired with radiation, it is sometimes given alone and most recently in combination with immuno-oncology agents. [11] These combinations have already demonstrated improved outcomes in certain kinds of lung cancer. [12]

Achieving overall survival benefit through combinations of immuno-oncology agents with radiotherapy has to-date proven to be a bit more elusive, but interesting clinical effects, called abscopal responses, have been observed that give us a great deal of hope for the future impact of such combinations. [13] An abscopal response occurs when tumors directly exposed to radiotherapy shrink and tumors outside of the irradiation zone in distant parts of the body also shrink or disappear.[14] Until recently, this phenomenon has been an extremely rare occurrence. In fact, just a handful of patients within 50 years of radiotherapy were reported to have such a response. An ongoing Phase 1 clinical trial has disrupted this trend and shown that when a specific radio-enhancer was given in combination with low dose radiotherapy, shrinkage of irradiated as well as non-irradiated tumors occurred in some patients. [15]

Moving forward, radio-enhancers hold the promise of delivering a higher rate of abscopal response across a broader range of cancer types. Similarly, the opportunity to combine new immuno-oncology therapies with checkpoint inhibitors may achieve a more potent immune effect in cancers. This approach may lead to a better outcome in common cancer types not currently responding to treatment, including prostate cancer.

The tide has turned

Improvements in overall survival rates for people living with a range of cancers such as prostate cancer, breast cancer, lung cancer and lymphomas, that were previously believed to be intractable, suggest that the tide is turning in the war on cancer. The current rate of progress in this endeavor is exponential and the next few years will be critical in shifting ever more patients’ care from palliative to life-prolonging, whilst simultaneously improving their quality of life by implementing safer treatments.

References:

[1] The American Cancer Society medical and editorial content team. Evolution of Cancer Treatments: Radiation. American Cancer Society. 2014 Jun 12. [Article]

[2] Foo J, Michor F. Evolution of acquired resistance to anti-cancer therapy. J Theor Biol. 2014 Aug 21;355:10-20. doi: 10.1016/j.jtbi.2014.02.025. Epub 2014 Mar 25. [Pubmed] [Article]

[3] Easton J. Immunotherapy: Why don’t more patients respond? University of Chicago School of Medicine. 2017 Dec 9. [Article]

[4] Homer C. Analysis determine true cost for CAR T-cell therapy. Healio: Hematology/Oncology. 2018 Apr 16. [Article]

 [5] Goodman A. Radioligand Therapy Achieves Responses in Metastatic Prostate Cancer. The ASCO Post. 2019 Mar 10. [Article]

[6] The American Cancer Society medical and editorial content team. Evolution of Cancer Treatments: Chemotherapy.” American Cancer Society. 2014 Jun 12. [Article]

[7] Khan H, Gucalp R, Shapira I. Evolving Concepts: Immunity in Oncology from Targets to Treatments.” J Oncol. 2015;2015:847383. doi: 10.1155/2015/847383. Epub 2015 Apr 28. [Pubmed] [Article]

[8] Bonilla FA, Oettgen HC. Adaptive immunity. J Allergy Clin Immunol. 2010 Feb;125(2 Suppl 2):S33-40. doi: 10.1016/j.jaci.2009.09.017. Epub 2010 Jan 12. [Pubmed] [Article]

[9] Noxopharm Limited. Idronoxil Confirmed as New Immuno-Oncology Drug. 2019 Apr 16. [Press Release]

 [10] Keshavarz-Fathi M, Rezaei N. Combination Therapy: Cancer Vaccines and Other Therapeutics. Vaccines for Cancer Immunotherapy: An Evidence-Based Review on Current Status and Future Perspectives; 2019. 13: 161-170. doi.org/10.1016/B978-0-12-814039-0.00013-8. [Article]

[11] Ingross G, Detti B, Scartoni D, Lancia A, Giacomelli I, Baki M, Carta G, Livi L, Santoni R. Current therapeutic options in metastatic castration-resistant prostate cancer. Semin Oncolog. 2018 Oct;45(5-6):303-315. doi: 10.1053/j.seminoncol.2018.10.001. Epub 2018 Oct 30. [Pubmed] [Article]

[12] For KEYTRUDA for injection. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 2018 Jun. [Prescribing Information]

[13] Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, Krainer M, Houede N, Santos R, Mahammedi H, Ng S, Maio M, Franke FA, Sundar S, Agarwal N, Bergman AM, Ciuleanu TE, Korbenfeld E, Sengeløv L, Hansen S, Logothetis C, Beer TM, McHenry MB, Gagnier P, Liu D, Gerritsen WR; CA184-043 Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014 Jun;15(7):700-12. doi: 10.1016/S1470-2045(14)70189-5. Epub 2014 May 13. [Pubmed] [Article]

[14] Piana, R. The Abscopal Effect: A Reemerging Field of Interest. The ASCO Post. 2018 Nov 25. [Article]

[15] Noxopharm Limited. Combination of Veyonda + Radiotherapy Delivers Clinical Benefits. 2019 Feb 6. [Press Release]