Since the early days of the COVID-19 pandemic, there were questions about how people in active cancer treatment would fare if they became infected with SARS-CoV-2.
The worries were due, in large part, to the effects that cancer and its treatments can have on the immune system. Now that COVID-19 vaccines are widely available, concerns have shifted to the safety and effectiveness of vaccination in this potentially vulnerable population. A study published June 5 in the journal Cancer Cell aims to allay those fears.
In a review of 200 patients with a wide spectrum of cancer diagnoses, researchers at Montefiore Health System and Albert Einstein College of Medicine in the Bronx, NY, found that after full vaccination, 94% of patients overall demonstrated seroconversion, which was determined by the presence of antibodies to the SARS-CoV-2 spike protein.
Response rates were very high among patients with solid tumors and were lower in people with certain blood cancers, but even the majority of those patients mounted an immune response.
“Studies from early in the pandemic found that cancer patients who get COVID-19 have higher rates of morbidity and mortality compared to the general population,” says senior co-author Amit Verma, director of the Division of Hemato-Oncology at Montefiore and professor of medicine and of developmental and molecular biology at Einstein, and associate director, translational science, Albert Einstein Cancer Center. “We really need efforts to protect these vulnerable patients from infection.
This study should help people feel reassured that these vaccines work very well, even in those receiving chemotherapy or immunotherapy.”
“This study confirms that there is no need for patients to wait for vaccination until they finish their chemotherapy or immunotherapy,” says senior co-author Balazs Halmos, director of the Multidisciplinary Thoracic Oncology Program at Montefiore, professor of medicine at Albert Einstein College of Medicine, and a member of the Albert Einstein Cancer Center (AECC).
“The side effects from vaccination seen in these populations were not substantially worse than in other groups. Not a single patient had to go to the emergency room or be admitted to the hospital because of side effects from the vaccines.”
This study was the largest of its kind to look at seroconversion rates in cancer patients who have been fully vaccinated. Previous studies have looked at much smaller populations or have analyzed antibody levels after only the first dose of two-dose vaccines.
In serum tests to look for IgG levels after vaccination, the researchers found that among patients with solid tumors, 98% showed seroconversion. Among patients with hematologic cancers, the rate of seroconversion was 85%.
Patients receiving some treatments fared worse than others. Those receiving therapies for blood cancers that work by killing B cells (such as rituximab or CAR T therapies) had seroconversion rates of 70%. For those who had recently had bone marrow or stem cell transplants, the rate was 74%. But those rates were still much higher than expected, the researchers say.
“Although those receiving treatments that affect B cells didn’t do as well, patients with blood cancers that affect the myeloid cells rather than the lymphoid cells had a pretty good response with regard to seropositivity,” says first author Astha Thakkar, a Montefiore hematologic oncology fellow. “This includes people with acute myeloid leukemia and myelodysplastic syndrome.”
The researchers say that one reason their data are so significant is that they include patients who had a broad range of cancers and who were undergoing a number of different treatments. “The patients themselves were also diverse and were representative of the patients we treat in the Bronx,” Halmos says. “About one-third were Black and 40% were Hispanic.”
Less than a year since the start of the COVID-19 pandemic, ten vaccines against SARS-CoV-2 have been approved for at least limited use, with over sixty others in clinical trials. This swift achievement has generated excitement and arrives at a time of great need, as the number of COVID-19 cases worldwide continues to rapidly increase.
Two vaccines are currently approved for full use, both built on mRNA and lipid nanotechnology platforms, a success story of mRNA technology 20 years in the making. For patients with cancer, questions arise around the safety and efficacy of these vaccines in the setting of immune alterations engendered by their malignancy and/or therapies.
We summarize the current data on leading COVID-19 vaccine candidates and vaccination of patients undergoing immunomodulatory cancer treatments. Most current cancer therapeutics should not prevent the generation of protective immunity. We call for more research in this area and recommend that the majority of patients with cancer receive COVID vaccinations when possible.
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: Astha Thakkar et al, Seroconversion rates following COVID-19 vaccination amongst patients with cancer, Cancer Cell (2021). DOI: 10.1016/j.ccell.2021.06.002
