Patients undergoing active chemotherapy had a lower immune response to two doses of the COVID-19 vaccine

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The COVID-19 pandemic has been an especially stressful time for cancer patients undergoing chemotherapy, which attacks not only the cancer, but also the immune cells needed to defend the body from infections. New research at the University of Arizona Health Sciences found that patients undergoing active chemotherapy had a lower immune response to two doses of the COVID-19 vaccine, but a third dose increased response.

“We wanted to make sure we understand the level of protection the COVID-19 vaccines are offering our cancer patients, especially as restrictions were being eased and more contagious variants were starting to spread,” said Rachna Shroff, MD, MS, chief of Gastrointestinal Medical Oncology at the UArizona Cancer Center and director of the Cancer Center Clinical Trials Office.

To answer this question, Dr. Shroff and a team of UArizona Health Sciences researchers looked at 53 Cancer Center patients on immunosuppressive active cancer therapy, such as chemotherapy.

They compared the immune response following the first and second dose of the Pfizer-BioNTech COVID-19 vaccine with that of 50 healthy adults. Their results were published online in the journal Nature Medicine.

After two vaccine doses, most of the cancer patients showed some immune response to the vaccine, meaning they had antibodies for SARS-CoV-2, the virus that causes COVID-19.

“We were pleasantly surprised,” said Deepta Bhattacharya, Ph.D., professor of immunobiology in the College of Medicine—Tucson and a member of the Cancer Center and BIO5 Institute. “We looked at antibodies, B cells and T cells, which make up the body’s defense system, and found the vaccine is likely to be at least partially protective for most people on chemotherapy.”

However, the immune response was much lower than in healthy adults, and a few of the patients had no response to the COVID-19 vaccine.

This translates to less protection against SARS-CoV-2, especially the delta variant that is now the dominant strain in the United States.

Twenty patients returned for a third shot, which boosted the immune response for most. The overall group immune response after the third shot reached levels similar to those of people who were not on chemotherapy after two doses.

The interdisciplinary research team was formed not long after the Pfizer-BioNTech vaccine was approved in late 2020. To get the clearest answer possible, they focused on patients with solid tumors, such as breast or gastrointestinal cancer, and excluded people on immunotherapy.

“The fact that we could answer this question in such a short time speaks to what can happen when you leverage the varied expertise we have within UArizona Health Sciences,” said Dr. Shroff, who also is a member of the BIO5 Institute.

“Cancer Center clinicians went above and beyond to enroll their patients in the study because we all had a unified goal to protect our patients.”


Implications for patients with cancer

Patients with cancer are at increased risk of severe illness from COVID-19 [15, 48–51]. In a study of 73 million patients in the USA, of whom 273,000 had been diagnosed with cancer in the last year and 16,570 were diagnosed with COVID-19, patients with cancer had greatly increased odds of COVID-19 infection (adjusted odds ratio (aOR) of 7; [52]). Odds of infection were highest for patients with recently diagnosed leukemia (aOR 12.2), non-Hodgkin’s lymphoma (aOR 8.5), and lung cancer (aOR 7.7).

Mortality is also higher in patients with cancer who develop COVID-19: patients with cancer and COVID-19 have a greater risk of mortality (14.9%) than patients with COVID-19 without cancer (5.3%) and patients with cancer without COVID-19 (4.0%) [52]. For patients diagnosed with a hematologic malignancy in the last 5 years, the increased risk of death has been estimated to be at least 2.5-fold, and for other cancers, at least 1.2-fold [48].

Because of the increased vulnerability of patients with cancer to COVID-19 infections and mortality, there is urgent interest in vaccinating this population expeditiously. Considerations around expected safety and efficacy differ by therapy based on their general mechanisms and associated immune alterations.

Considerations for patients treated with cytotoxic chemotherapies

Cytotoxic chemotherapies interfere with DNA replication, synthesis, and cell cycle progression. Lymphocytes proliferate rapidly as part of activation and so are suppressed by these therapies [53]. However, suppression is not complete and immune responses can nevertheless be elicited to vaccination while on cytotoxic chemotherapy. Patients with acute lymphoblastic leukemia, in which the immune system is directly impacted by disease as well as treatment, can still generate immune responses after vaccination, ranging from 10 and 27% of patients immunized with hepatitis B and meningococcal subunit vaccines, respectively, to 100% of patients immunized with diphtheria and tetanus toxoid vaccines [54–56].

In studies of responses to the annual inactivated influenza vaccine in patients with cancer, 10–42% of patients with hematologic malignancies responded to one dose of influenza vaccine [57–59], with additional responses with a second dose [57, 58]. Higher responses are seen in patients with solid tumors on chemotherapy [60]: at least 78% in patients with lung cancer [61] and 81% of patients with breast cancer [59] on mild to moderately immunosuppressive regimens. When given between cycles of chemotherapy for lung or breast cancer, timing relative to the last cycle may matter, though estimates of the optimal day varies [60, 62, 63].

Vaccination was well-tolerated in these studies. Infectious Diseases Society of America (IDSA) and The European Conference on Infections in Leukemia (ECIL) guidelines recommend yearly vaccination with inactivated influenza vaccine—an exception is during intensive therapy (e.g., induction and consolidation therapy for acute leukemias) given likely poor response, but considered reasonable given seasonal nature of influenza [64, 65].

Hepatitis B subunit and pneumococcus vaccinations may also be recommended even during chemotherapy [65, 66]. Titers can be helpful to assess need for revaccination [64, 66]. Higher doses or boosters are employed to enhance immunogenicity to inactivated influenza, pneumococcal polysaccharide, and hepatitis B subunit vaccines [64–66]. Overall, with the exception of during periods of intensive chemotherapy, patients undergoing chemotherapy are expected to generate protective responses with COVID-19 vaccination.

Considerations for patients treated with targeted therapies

Targeted therapies include receptor tyrosine kinase inhibitors (TKIs) such as erlotinib, sunitinib, and imatinib or monoclonal antibodies such as trastuzumab. Targeted therapies should not directly cause immunosuppression as part of their mechanism of action, but may have unintended inhibitory effects on antigen presenting cell function, T cell activation [67] and B cell signaling [68].

Nevertheless, patients treated with sunitinib or sorafenib develop seroprotection with the influenza vaccine comparable to healthy controls [69]. Similarly, patients with chronic myelogenous leukemia (CML) on TKIs develop seroprotection after the influenza vaccine at reduced but still substantial rates around 40% [68]. There was also no difference in seroprotection against influenza when comparing controls versus patients with breast cancer treated with anti-HER2 monoclonal antibody trastuzumab [70].

Ibrutinib, an inhibitor of Bruton tyrosine kinase essential for B-cell receptor signaling, maturation, and immunoglobulin synthesis, unsurprisingly impairs responses, producing seroconversion in only 7–26% of patients after influenza vaccination [71, 72], though 75% of patients on ibrutinib were able to respond to subunit vaccines against varicella zoster [73].

The ECIL group recommends that patients with CML on TKIs receive the yearly inactivated influenza vaccine and to be vaccinated against Streptococcus pneumoniae. Thus, it is reasonable to expect that patients being treated with targeted therapies will generate protective responses with COVID-19 vaccination.

Considerations for patients treated with immune checkpoint inhibitors

Immune checkpoint inhibitors target immunosuppressive pathways such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that are upregulated in tumor-reactive T cells, thereby enhancing immune responses and endogenous anti-tumor activity. While cancers such as lung cancers and comorbidities such as smoking have been associated with higher severity of COVID-19 infections [50, 74, 75], concurrent immune checkpoint inhibitor treatments for patients with lung cancer have not been associated with more severe infections or mortality when adjusted for smoking status [76].

Checkpoint inhibitors incur a risk of immune-related adverse events (IRAEs), at a rate of 17–48% for any grade and 5–8% severe grade, depending on the specific therapy [77]. There is a theoretical concern that vaccination could stimulate an overexuberant immune response and increase IRAEs in patients actively treated with immune checkpoint inhibitors. A 2018 study of 23 patients on immune checkpoint inhibitors who received the influenza vaccine found a high rate of IRAEs (52%).

However, subsequent larger studies including three with non-vaccinated comparison groups did not show higher frequencies of IRAEs with vaccination [78, 79]. Moreover, immune checkpoint inhibitors are considered safe to use in patients with chronic HIV, hepatitis B, and hepatitis C infections, suggesting that stimulation by viral antigens is safe even in the context of bona fide infection [79].

Furthermore, influenza vaccine-induced seroprotection is generally not substantially diminished [78, 80]. Thus, we expect that patients on immune checkpoint inhibitor therapy should make protective responses with COVID-19 vaccination. Whether IRAEs increase after COVID-19 vaccinations warrants close study. In the interim, it may safe from a cancer treatment perspective to delay immune checkpoint inhibitor treatment in some settings [81].

Considerations for patients treated with lymphodepleting or plasma cell depleting therapies

Lymphodepleting and plasma cell depleting therapies include anti-CD20 antibodies used for treatment of hematologic malignancies and autoimmune diseases as well as anti-CD38 monoclonal antibodies used in the treatment of multiple myeloma. Anti-CD20 treatments deplete peripheral B cells for at least 4 months [82, 83] and during this period impairs immune responses to vaccination including those against influenza, Streptococcus pneumoniae, and Haemophilus influenza [84, 85]. T cells may also be reduced as a consequence of the reduced pool of antigen-presenting B cells [84, 86].

Adoptive cellular immunotherapy targeting B cells to treat hematologic malignancies include CAR-T cells against CD19, which is expressed by nearly all B cells. Anti-CD19 therapy is B cell depleting, with high likelihood of subduing antibody responses to vaccination and increasing susceptibility to severe disease from COVID-19. There is little data on the immunogenicity and safety of vaccinations after CD19-targeted CAR-T cell therapy.

Expert opinion of a committee of the National Comprehensive Cancer Network (NCCN) recommends that vaccination should be delayed for at least 3 months post-hematopoietic cell transplant or cellular therapy [87]. Previously established plasma cells may not be affected by anti-CD19 therapies owing to their lack of CD19 expression, so vaccine or pathogen-specific serum immunoglobulins may be maintained post-treatment [88].

Anti-CD38 therapies target plasma cells and are therefore also B-cell depleting. T cell activation may conversely be enhanced due to the expression of CD38 on immunosuppressive cell populations [89]. In patients with multiple myeloma treated with daratumumab, the frequency of normal plasma cells in bone marrow samples is decreased as well as levels of polyclonal immunoglobulins.

However, IgG levels and induction of protective antibody titers were intact against Streptococcus pneumoniae, Haemophilus influenzae B and seasonal influenza at a median of 2 months after treatment, presumably due to a subset of plasma cells expressing reduced levels of CD38 that escape treatment [90].

In practice, it is recommended that vaccines be given at least 6 months after anti-B cell therapy due to likely futility [64, 66]. Despite expected reduced responses, an exception is made for the influenza vaccine which is given yearly, though ideally at least 2 weeks prior to lymphodepleting chemotherapies [91]. Patients on anti-B cell therapy are at especially high risk for severe disease and death from COVID-19 and prolonged viral shedding [92, 93], and thus, a similar exception would be reasonable to apply to COVID-19 vaccination.

Considerations for patients treated with radiation

Radiation therapy is commonly used for patients with malignancies both in the curative and palliative settings. While it is known that radiation involving a large part of the body can indeed have impact on the bone marrow, it is rare for radiation to have a significant impact on the immune system to the point where vaccination would not be recommended. The main situation for radiation to affect immune cell generation is in the event of total body irradiation (TBI) given for marrow suppression prior to stem cell transplantation or other rare situations where patients are receiving total lymph node or spine irradiation. Therefore, most patients treated with radiation should generate protective immunity responses to COVID-19 vaccines.

reference link :https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910769/


More information: Rachna T. Shroff et al, Immune responses to two and three doses of the BNT162b2 mRNA vaccine in adults with solid tumors, Nature Medicine (2021). DOI: 10.1038/s41591-021-01542-z

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