Safety of Inactivated Vaccines in Patients Receiving Immune Checkpoint Inhibitors

Austin Kurkowski, PharmD, BCOP
Hematology/Oncology Clinical Pharmacist
Cleveland Clinic Taussig Cancer Institute
Cleveland, OH

Grace Martin, PharmD, BCOP
Cancer Care Pharmacy Clinical Coordinator
The University of Kansas Health System
Kansas City, KS

Introduction
Immune checkpoint inhibitors upregulate the body’s immune system through T-cell activation and prevent malignant cells from evading apoptosis through 3 main mechanisms, including inhibition of programmed cell death 1 (PD-1), PD ligand 1 (PD-L1), and cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4).^1,2 These drugs carry a unique risk for immune-related adverse events (irAEs) which can manifest in many organ systems.

The most common irAEs include rash, pruritus, colitis, hepatitis, pneumonitis, hypo- or hyperthyroidism, hypophysitis, and adrenal insufficiency. These adverse events vary in severity and may lead to treatment delay or discontinuation. One meta-analysis described an incidence of grade ≥3 irAEs between approximately 7% and 55%.³ It is difficult to predict which patients will have irAEs, and when they may occur. New antigen exposure from inactivated vaccines allows for T-cell interactions that may drive increased irAEs.^4,5

Literature describing the incidence and severity of irAEs with the use of inactivated vaccines is limited and only describes the risks associated with influenza vaccination. In 2018, one study showed that patients receiving PD-1 inhibitor therapy concurrent with inactivated influenza vaccines had a higher incidence of grade 3 or 4 irAEs than historical controls.⁶ More recent studies, however, contradicted these data.^4,7 Few primary studies evaluated inactivated vaccines other than influenza vaccines concurrently with immunotherapy. There are limited published data of vaccines in patients who are receiving immunotherapy beyond nivolumab or pembrolizumab, or in combination with chemotherapy.^4,6-8

Methods
At the University of Kansas Health System, various inactivated vaccines are administered to patients who are receiving immune checkpoint inhibitor therapy. Currently, no institutional policies are in place for the use of inactivated vaccines in patients who are receiving immunotherapy. This study attempted to determine the relative incidence rate of irAEs requiring therapeutic intervention in the vaccinated versus a control group. We also assessed the rates of therapy delay or discontinuation due to irAEs. A therapeutic intervention for an irAE was defined as a delay of immune checkpoint inhibitor treatment by ≥14 days after the expected date of therapy for cycle 2 or beyond, discontinuation of treatment, or the addition of supportive therapy. Supportive therapy was defined as the addition of a medication for the management of irAEs, such as corticosteroids or other immunosuppressants. Only irAEs that newly occurred after receipt of a vaccine and an immune checkpoint inhibitor were included.

Study Population and Results
This study included a total of 213 patients; 71 in the vaccinated cohort and 142 in the control cohort (1:2 vaccinated to control matching was done based on age and immune checkpoint inhibitor received). Patients in the vaccinated cohort were required to have received an inactivated vaccine 30 days before or 60 days after the administration of immune checkpoint inhibitor. Patients were reviewed for demographics (age, race, gender), malignancy, and type of vaccine and immunotherapy.

The most common malignancies included non-small-cell lung cancer, melanoma, renal-cell carcinoma, small-cell lung cancer, and head and neck cancer. The inactivated influenza vaccine was the most frequently (N = 48) administered, followed by pneumococcal vaccines (PPSV23, N = 19; PCV13, N = 8) and the Tdap vaccine (N = 8). Other vaccines included inactivated polio, recombinant zoster, and hepatitis A. Twelve patients received more than 1 type of inactivated vaccine. Those in the vaccinated cohort most often received nivolumab monotherapy (40.8%) or pembrolizumab monotherapy (35.2%); fewer patients received nivolumab plus ipilimumab (5.6%), nivolumab plus chemotherapy (2.8%), or pembrolizumab plus chemotherapy (9.9%), or other therapies (5.7%).

A total of 22.5% (N = 16) of vaccinated patients had an irAE requiring an intervention versus 26.8% (N = 38) of patients in the control cohort (P = .50). No significant differences were observed in the rates of therapy delays resulting from irAEs (vaccinated 9.9% vs control 9.2%; P = .87) or discontinuations resulting from toxicity (vaccinated 9.9% vs control 9.9%; P = 1.00). All patients requiring the use of supportive therapy received a corticosteroid, and no difference was seen in the rate of patients requiring additional therapy between the 2 cohorts (vaccinated, 18.3%; control, 25.4%; P = .25). Common irAEs requiring intervention included rash or pruritus, pneumonitis or dyspnea, diarrhea or colitis, and transaminitis.

Patients who started immune checkpoint inhibitor therapy before vaccination had a median time from vaccination to intervention of 60 days (range, 0-368 days). In patients who were vaccinated first, the median time from initiation of immunotherapy to intervention was 74.5 days (range, 14-86 days). For the 1 patient who received a vaccine on the same day that immunotherapy was initiated, the time to intervention was 71 days.

Discussion and Key Takeaways
Expanding the scope of understanding how various inactivated vaccines and immunotherapy work in concert to cause irAEs will give clinicians an increased knowledge needed to engage in informed medical decision-making. This study indicates that patients may safely receive immune checkpoint inhibitors with inactivated vaccines, and increased receipt of appropriate vaccines can provide optimized care to an already vulnerable patient population.

Our study used a more stringent time frame than previous studies, limiting the receipt of a vaccine to only 30 days before an immune checkpoint inhibitor administration.4 We allowed for vaccination up to 60 days after immune checkpoint inhibitor administration, given the long half-life of these medications. It was also notable that no patients required nonsteroidal immunosuppressive therapy, such as infliximab. We therefore presumed that none of the patients’ irAEs were refractory to their management.

A noteworthy but unexpected irAE in two patients who received vaccines was graft-versus-host disease (GVHD) reactivation after the initiation of immune checkpoint inhibitor therapy, which followed allogeneic stem-cell transplant. A total of four patients in the vaccinated cohort had a history of allogeneic stem-cell transplant. These patients were not excluded, to facilitate a wholistic and real-world perspective. The high incidence of GVHD in this setting has been described in previous studies.9,10 In both cases, the complex clinical scenario made it difficult to definitively correlate acute GVHD with immune checkpoint inhibitor therapy, but the medications may be contributing factors, given the acute changes in clinical condition and proximity to receipt of immune checkpoint inhibitor therapy.

To our knowledge, this study is one of the first studies to include data of inactivated vaccines beyond influenza and with regimens combining traditional chemotherapy and checkpoint inhibitor therapy. The results in our study are congruent with a 2017 study that showed that routine vaccination in patients receiving immunotherapy did not increase the number or severity of adverse events.¹¹ This is the only other study that included data on a vaccine other than influenza.

Future Directions and Conclusion
The risk for patients who are not vaccinated may significantly outweigh the risk for irAEs. Future studies could include measuring the incidence of vaccine-preventable infections and its impact on patients’ morbidity and mortality. The pharmacoeconomic impact of patients who are not receiving appropriate vaccinations should also be considered.

In this study, immune checkpoint inhibitor treatment delays and discontinuations were minimal and similar between patients who were vaccinated and those who were not, indicating that patients who are receiving such treatment should not expect to have their duration of therapy influenced by the administration of an inactivated vaccine. Providers should therefore continue to recommend inactivated vaccines to the appropriate patients.

To our knowledge, this is one of few studies that provides information on the use of inactivated vaccines beyond influenza. Our findings confirm that vaccination is a safe, guideline-recommended practice.

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