For more than fifty years, we have been waging the war on cancer. While we are better than ever at treating the disease, yet cancer still claims thousands of lives.
You may be familiar with standard cancer therapies such as chemotherapy, radiation, and surgery. Recently, immunotherapy has emerged as another important treatment option for some cancers, such as melanoma and Merkel cell carcinoma (MCC). Both melanoma and MCC are skin cancers but arise from different cell types.
While our immune system can detect and destroy cancer cells, cancer cells are able to trick and dodge our immune system. For example, some cancer cells can change their surface to make them less visible to immune cells, while others express proteins that deactivate our immune response. Immunotherapy aims to foil cancer’s trick by reactivating the immune system to kill cancer cells.
One type of immunotherapy uses immune checkpoint inhibitors (ICIs). T cells, immune cells capable of killing pathogen infected cells as well as cancer cells, determine whether to let a cell live or die by detecting immune checkpoint proteins on the surface of our cells. In healthy bodies, immune checkpoint proteins prevent the immune system from going overboard and damaging healthy tissues. However, cancer cells often exploit these checkpoints to avoid immune detection. For example, when PD-1, present on the surface of our T cells, binds to its partner protein PD-L1 found on the surface of some cancer cells, it tells the T cells not to kill that cancer cell. Inhibiting the interaction between PD-1 and PDL-1 is achieved with ICIs, anti-PD-1, or anti-PDL-1. This allows our immune cells to recognize and kill cancer cells.
Metastatic melanoma and MCC patients have greatly benefited from ICI therapies partly because of the high mutational burden in these cancers and the presence of Merkel cell polyoma viral proteins in MCC cells. Standard protocols include standard frequency doses (usually every 2-3 weeks) of ICI therapy until disease progression or discontinuation of therapy after two years. Many patients, however, develop progressive disease after ICIs are discontinued.
In a recent study, Dr. Shailender Bhatia, a professor in the Clinical Research Division, and his team examined whether reducing ICI dosing frequency would improve patient outcomes and save money and time. Toward this goal, Dr. Lisa Tachiki, assistant professor in the Clinic Research Division, took the lead role on Dr. Bhatia’s team conducting a retrospective analysis of patients with advanced melanoma or MCC who were treated initially at standard frequency dosing with anti-PD-1 or anti-PDL-1 inhibitors but who later transitioned to a reduced frequency dosing (typically every 3 months) at Fred Hutch between January 2014 and June 2021. “Optimizing dose frequency may be an alternative way to extend the benefits of this expensive class of drugs,” the authors said.
As an alternative to indefinite treatment at standard frequency or abrupt discontinuation of ICI at an arbitrary timepoint, reduced frequency of dosing may provide a sustainable option for extending treatment duration. Long-term and efficacy data gathered from patients who received reduced-frequency dosing regimen after having achieved disease control with standard frequency dosing of ICIs suggest sustained immune activation. In addition, reduced frequency dosing not only allowed for an extension of the treatment beyond the standard 2-year period, but also reduced the cumulative drug costs and clinic time. “The reducing frequency dosing strategy may provide an alternative approach to extend the duration of therapy, with substantially lower financial and logistical burden for patients as compared to the commonly used standard frequency dosing approach for 2 years of treatment.” This is especially important because “rising healthcare expenditures necessitate the development of sustainable and adaptive treatment strategies that reduce resource utilization without compromising patient care.”
Drs. Tachiki and Bhatia continue to validate their findings through ongoing pharmacokinetic and pharmacodynamic studies, including PD-1 receptor-occupancy, in blood samples from patients receiving ICI at different doses and schedules. Their findings support further investigation into ICI dose optimization studies, particularly important in low- and middle-income countries where access to ICI is limited due to its high cost.
This work was funded by the National Cancer Institute, Kelsey Dickson Merkel Cell Carcinoma Fund, the MCC patient gift fund at the University of Washington, and the Kuni Foundation Discovery Grant.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Drs. Lisa Tachiki, Evan Hall, Joshua Veatch, Paul Nghiem, John A. Thompson and Shailender Bhatia contributed to this study.
Tachiki LML, Hippe DS, Williams Silva K, Hall ET, McCamy W, Fritzsche D, Perdue A, Majovski J, Pulliam T, Goldstein DA, Veatch J, Ho J, Nghiem PT, Thompson JA, Bhatia S. Extended duration of treatment using reduced-frequency dosing of anti-PD-1 therapy in patients with advanced melanoma and Merkel cell carcinoma. Cancer Immunol Immunother. 2023 Nov;72(11):3839-3850. doi: 10.1007/s00262-023-03539-8. Epub 2023 Sep 21. Erratum in: Cancer Immunol Immunother. 2023 Dec;72(12):4471.
Joss Landazuri is a PhD candidate at the University of Washington in the Microbiology program working at the intersection of biomedical science, public policy, and science diplomacy. As a Latina scientist, communicator, and policy advocate, she is passionate about leveraging her academic training, personal background, and cultural heritage to engage underserved communities in both science and the policymaking process.
For the Media