Immunotherapy in Cancer: Rebooting Natural Defenses

Through the ages, cancer’s reputation has been notorious. Although most diseases wax and wane, until the middle of the past century, most people perceived cancer as a painful, relentless march toward death. Occasionally, however, clinicians observed cases of spontaneous remission. They questioned whether remarkable recovery was actually a misdiagnosis or some inexplicable self-repair mechanism.¹ Beginning in the 1970s, some investigators looked at spontaneous regression in melanoma and asked, “Could the patient’s immune system have kicked in, effectively combating the tumor?” The science of immunotherapy had emerged.²

Over the following 40 years, the idea of using the patient’s own immune system to combat cancer took hold, albeit slowly. The FDA approved the first cancer immunotherapy agent, interferon alpha, in 1986. In 1992, the FDA approved interleukin-2 for cancer. Things were then quiet for almost 20 years. But since 2010, the FDA has approved a handful of effective immunotherapies.²

Just a small number of immunotherapies are available. Let’s look at the monoclonal antibodies with the most prescribing activity lately (Table 1^3-6).

The agents discussed in Table 1^3-6 are called immune checkpoint blockers, and they are divided into cytotoxic T-lymphocyte antigen-4 (CTLA-4) receptor and programmed death-1 (PD-1)/programmed death ligand-1 agents. In addition, a newer term is microsatellite instability. It reflects a change in tumor DNA, in which the number of repeats of microsatellites (short, repeated DNA sequences) differs from the number of repeats in the patient’s inherited DNA. A defect in the ability to repair mistakes during DNA copying may be the cause.^3-6

All the most recent immunotherapies require patients to carry specific biomarkers on their tumors. Some patients have had dramatic responses, indicating that the biologic restored antitumor immune surveillance. However, overall, these agents work only in select cancers and usually in a subset of patients with those cancers.^7,8

Investigators think that because cancer immunotherapies are usually used after first-line treatments (eg, conventional chemotherapy), patients’ immune systems are already weakened by advanced disease and/or previous therapies. Restoring the antitumor immune function is harder than in conditions of more robust immune function. Administering personalized cancer immunotherapies earlier—a strategy that is emerging—may lead to better response rates.⁹

Chemotherapy usually creates a rapid tumor response. With immunotherapy, some patients will respond early, but immunotherapies cause immune cells to infiltrate tumors and then destroy them. On an x-ray or a computed tomography scan, tumors often appear enlarged before they begin to shrink, suggesting malignancy growth, called pseudo-progression. Routine scans do not differentiate between malignant tumor tissue and normal infiltrating immune system cells and fluid.^10,11 Tumor shrinkage may take more time than expected with traditional treatments.¹²

Many patients will eventually respond, and response can last years, even after immunotherapy ends.¹³ In several of the approved indications, patients have experienced more than 6 months of progression-free survival,¹⁴ a significant improvement over traditional treatments.

Cancer immunotherapies are very costly,¹⁵ and often the co-payment can be staggering for patients. Patients need to work with a specialty pharmacy or a cancer treatment clinic to obtain these biologics.

Immunotherapies have few drug interactions (Table 2^3-6).

In general, these agents are not as toxic as traditional chemotherapies, and most adverse effects (AEs) are low-grade. Ipilimumab has been associated with rash, diarrhea/colitis, liver toxicity, and endocrine toxicity (pituitary dysfunction and diabetes), with about a quarter of patients experiencing dose-limiting toxicities.⁶ Atezolizumab, nivolumab, and pembrolizumab may cause diarrhea, endocrine and liver toxicity, and a rash. Just 15% of patients experience these in a magnitude that is dose-limiting, however.^3-5

So what should pharmacists know about immune-related AEs? The most important thing is to educate patients to recognize AEs early. Nonspecific complaints may indicate endocrine (pituitary) toxicity. Diarrhea is a particular concern for patients, and it most often starts 6 to 8 weeks after treatment begins.¹⁶

Corticosteroids are effective, especially for diarrhea, and clinicians should be cautious not to taper too quickly. In patients whose diarrhea becomes severe, clinicians may consider high-dose steroids, infliximab, or mycophenolate mofetil.^17,18

Combination immunotherapies are associated with higher toxicity rates than single-agent immunotherapy. Watch patients who are on combination (CTLA-4/PD-1) therapy closely for multiple or early AEs.^17,18

Community pharmacists can support patients who are on immunotherapies, especially by educating them about AEs and providing encouragement.

Jeannette Y. Wick, RPh, MBA, FASCP, is the associate director of the Office of Pharmacy Professional Development at the University of Connecticut School of Pharmacy in Storrs.

References

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