Immunotherapy: Staring Cancer Right in the Eye
For 2016, American health care providers will have delivered bad news to an estimated 1.7 million patients. “You have cancer,” they’ll have said. Thirty-five percent of these patients will eventually die from the disease, which actually is an improvement over past decades because of better cancer treatments.
For 2016, American health care providers will have delivered bad news to an estimated 1.7 million patients. “You have cancer,” they’ll have said. Thirty-five percent of these patients will eventually die from the disease, which actually is an improvement over past decades because of better cancer treatments.1
Older treatments (eg, chemotherapy and radiation) are associated with formidable adverse effects. Fortunately, immunotherapy, the novel therapeutic strategy, takes a “fight fire with fire” approach by addressing some of the shortcomings associated with traditional cancer treatments.
Oncologists have long believed that the slashburn-poison approach (ie, surgery, radiation, antineoplastics) was insufficient, that we needed to target cancer’s molecular mechanisms and their effects on the immune system. Within the past 15 years, oncology researchers have made tremendous progress. Immunotherapy, also called biologic therapy or biotherapy, is a laudable breakthrough.2,3
Agents classified as immunotherapy either stimulate a patient’s immune system to recognize and attack cancer cells or augment it with immune system components. Treatments (eg, monoclonal antibodies, cytokines, adoptive T-cell transfer, anti-cancer vaccines, immune checkpoint inhibi- tors, oncolytic viruses) make tumor cells visible to our defenses and destroy them.2,3
Cancer and the Immune System
The immune system involves organs, specialized cells, and substances (eg, cytokines) that recognize other substances as foreign, or “non-self,” and activate when they sense intruders. Most of the time, it works efficiently to identify antigens. Cancer cells—cells that start in a patient’s organs, have aberrant apoptosis (programmed cell death), and grow rapidly—challenge the immune system in that it often fails to see them as foreign until the cancer has caused considerable damage. The immune system’s response may be inadequate in the face of rapidly growing cells, or the cancer cells themselves may secrete substances that fool the immune system.2,3 Immunotherapies (table 2,3) boost the immune system, lessening the chance that cancer can circumvent an immune response. They increase recognition of cancer cells and strengthen that response.
Which Tumors, Which Therapy?
Some immunotherapy has an established place in medical history. Researchers developed the Bacillus Calmette-Guérin vaccine against tuberculosis, discovering later that it provides a robust anti-tumor response when given to patients with bladder cancer.4 Approved in 1990, it is still the standard of care.5
Certain malignancies, especially renal cell cancers and melanomas, appear to be immunogenic and more resistant to conventional chemotherapy than others. Yet some immunogenic tumors still respond when exposed to high-dose cytokine therapy (eg, interleukin-2).6 Researchers tried administering cytokines with chemotherapy, but high rates of toxicity and insignificant improvements in survival outcomes stalled these efforts in all but a small subset of patients.7,8
The cornerstone of advances in immunotherapy was the realization that cancer cells and the immune system have a unique relationship. In cancer, antigen presentation is necessary, but still insufficient, to activate the immune system. Therefore, a second action, costimulatory signals to activate cytotoxic T cells, is necessary.9 Researchers’ discovery of inhibitory pathways, which squelch T-cell activation and promote tumorigenesis,10,11 shed light on a potential mechanism: blocking these pathways. The concept of checkpoint inhibitors was born, and agents developed along this line of thought have provided durable clinical responses in several cancers, even a few not considered immunogenic in the past.12-15 Immunotherapy’s success builds on our understanding of elimination, equilibrium, and escape (online figure 16). Looking at tumors as just a mass of cancer cells is short-sighted. Cancer is a constellation of factors, including stromal cells, immune cells, fibroblasts, and endothelial cells, each of which contributes to a tumor’s malignant potential and response to the immune system.16
Different Approach, Different Trajectory
Pharmacists need to understand that immunotherapy—checkpoint inhibitors, in particular—is unique. Three points are critical:
• Some patients will experience early tumor responses, just as they do with chemotherapy. Immunotherapies destroy tumors by causing immune cells to infiltrate them. Tumors often appear enlarged on an x-ray or computed tomography scan before they begin to shrink (called pseudo-progression). Routine scans do not differentiate between malignant tumor tissue and normal infiltrating immune system cells and fluid.17,18 A tumor may swell as the immune system kicks in, suggesting malignancy growth. Tumor shrinkage may take more time than expected with traditional treatments.19
• Many patients will eventually respond, and that response can last years, even after immunotherapy ends.19
• Although melanoma outcomes have been linked to the development of vitiligo and responses to targeted therapies and cytotoxic chemotherapy are sometimes associated with specific toxicities,20 toxicity does not predict response to immunotherapy.
The pseudo-progression phenomenon has led to new immune response criteria that is used in lieu of the traditional Response Evaluation Criteria In Solid Tumors.19 So that they can exclude pseudo-progression, oncologists discontinue immunotherapy no sooner than 4 weeks after an initial scan showing progression.
The Work Continues
Some of immunotherapy’s challenges include measuring response and accurate, noninvasive pharmacological monitoring.17,18 The need for meaningful, accurate diagnostic tests that promptly reflect immunotherapies’ effects is apparent. For example, for oncolytic viruses, having tests similar to those used in HIV would allow physicians to base treatment on the actual level of the virus within the target cells.2
Immunotherapy has changed many an individual’s cancer prognosis, often lengthening time to progression and sometimes generating a cure. And the news continues to improve: researchers are using immunotherapy in other conditions. In Alzheimer’s disease (AD), several biologics (aducanumab, saracatinib, solanezumab) are in clinical trials and experts are cautiously hopeful that they will stop or significantly delay AD’s progression.21 With time, immunotherapy may offer new hope for many systemic diseases
Ms. Wick is a visiting professor at the University of Connecticut School of Pharmacy.
- Cancer statistics. National Cancer Institute website. www.cancer.gov/about-cancer/understanding/statistics. Accessed December 15, 2016.
- Mavani HJ, Wick JY. Oncology’s Trojan horse: using viruses to battle cancer. Consult Pharm. 2016;31(12):678-685.
- Menon S, Shin S, Dy G. Advances in cancer immunotherapy in solid tumors. Cancers (Basel). 2016;8(12). pii: E106.
- Mungan NA, Witjes JA. Bacille Calmette-Guérin in superficial transitional cell carcinoma. Br J Urol. 1998;82(2):213-223.
- Sylvester RJ, van der Meijden AP, Witjes JA, Kurth K. Bacillus calmette-guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a meta-analysis of the published results of randomized clinical trials. J Urol. 2005;174(1):86-91; discussion 91-92.
- Klapper JA, Downey SG, Smith FO, et al. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma: a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer. 2008;113(2):293-301. doi: 10.1002/cncr.23552.
- Atzpodien J, Kirchner H, Rebmann U, et al. Interleukin-2/interferon-alpha2a/13-retinoic acid-based chemoimmunotherapy in advanced renal cell carcinoma: results of a prospectively randomised trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). Br J Cancer. 2006;95(4):463-469.
- Krauze MT, Tarhini A, Gogas H, Kirkwood JM. Prognostic significance of autoimmunity during treatment of melanoma with interferon. Semin Immunopathol. 2011;33(4):385-391. doi: 10.1007/s00281-011-0247-y.
- Harding FA, McArthur JG, Gross JA, Raulet DH, Allison JP. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature. 1992;356(6370):607-609.
- Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity.1995;3(5):541-547.
- Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704. doi: 10.1146/annurev.immunol.26.021607.090331.
- Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123-135. doi: 10.1056/NEJMoa1504627.
- Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627-1639. doi: 10.1056/NEJMoa1507643.
- Garon EB, Rizvi NA, Hui R, et al; KEYNOTE-001 Investigators. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018-2028. doi: 10.1056/NEJMoa1501824.
- Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-723. doi: 10.1056/NEJMoa1003466.
- Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011;331(6024):1565-1570. doi: 10.1126/science.1203486.
- Russell SJ. Harnessing viruses treat cancer. Molecular Medicine Department and Division. Mayo Clinic website. www.mayo.edu/research/departments-divisions/department-molecular-medicine/harnessing-viruses-treat-cancer. Accessed September 15, 2016.
- Wong H, Lemoine NR, and Wang Y. Oncolytic viruses for cancer therapy: overcoming the obstacles. Viruses. 2010:2(1):78-106. doi: 10.3390/v2010078.
- Hodi FS, Hwu WJ, Kefford R, et al. Evaluation of immune-related response criteria and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab. J Clin Oncol. 2016;34(13):1510-1517. doi: 10.1200/JCO.2015.64.0391.
- Gyorki DE, Callahan M, Wolchok JD, Ariyan CE. The delicate balance of melanoma immunotherapy. Clin Transl Immunology. 2013;2(8):e5. doi: 10.1038/cti.2013.5.
- Mendiola-Precoma J, Berumen LC, Padilla K, Garcia-Alcocer G. Therapies for prevention and treatment of Alzheimer’s Disease. Biomed Res Int. 2016;2016:2589276. doi: 10.1155/2016/2589276.