COVID-19 Vaccines For Patients With Cancer: Benefits Likely Outweigh Risks

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(2021) 14:38Hwang et al. J Hematol n AccessREVIEWCOVID‑19 vaccines for patients with cancer:benefits likely outweigh risksJoyce K. Hwang1†, Tian Zhang2,3*† , Andrew Z. Wang4 and Zihai Li5AbstractLess than a year since the start of the COVID-19 pandemic, ten vaccines against SARS-CoV-2 have been approvedfor at least limited use, with over sixty others in clinical trials. This swift achievement has generated excitement andarrives 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 ofmRNA technology 20 years in the making. For patients with cancer, questions arise around the safety and efficacy ofthese vaccines in the setting of immune alterations engendered by their malignancy and/or therapies. We summarizethe 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.Keywords: COVID-19, COVID-19 vaccines, SARS-CoV-2 virus vaccines, COVID-19 and cancer, Vaccination, Cancertherapies, Patients with cancer and COVID-19Natural immunity to SARS‑CoV‑2Protective immunity against viral infections involveshumoral immunity and cell-mediated immunity (Fig. 1).Humoral immunity is provided by B lymphocytes whichproduce antibodies which may neutralize virus by binding virus and preventing its entry into host cells. Cellmediated immunity includes macrophages and CD8 cytotoxic T lymphocytes, which eliminate infected cells. CD4 T lymphocytes help to activate B and CD8 T cells,which promote the generation of highly effective antibody responses and memory. C D4 helper T cell subsetsinclude Th1 which promotes cell-mediated immunityand opsonizing IgG antibodies, and Th2 which promotesIgE antibodies and, broadly, allergic-type inflammation.Following infection, antigen-specific memory B and T*Correspondence: tian.zhang2@duke.edu†Joyce K. Hwang and Tian Zhang contributed equally to this work2Division of Medical Oncology, Department of Medicine, Duke CancerInstitute, DUMC Box 103861, Durham, NC 27710, USAFull list of author information is available at the end of the articlecells persist and recall immune responses upon repeatencounter. In a viral infection, these protective immuneresponses are initiated by professional antigen-presentingcells such as dendritic cells, which capture, process, anddisplay viral peptides to MHC molecules to prime naïveantigen-specific T cells in the secondary lymphoid tissues. Productive T cell priming often requires additionalstimulatory cytokines and co-stimulatory molecules. Thegoal of a vaccine is to provide stimulation by the desiredantigen(s) in a context that mimics infection enough toelicit protective memory immunity with a tolerable safetyprofile. Productive immunogenic vaccines often requireadjuvants and/or a "prime-boost" strategy of repeateddoses to enhance durable immune responses.What immune responses are desired for protectiveimmunity against SARS-CoV-2? Re-challenge modelsin rhesus macaques indicated that primary exposureto SARS-CoV-2 is protective against re-infection [1].Convalescent patients after COVID-19 infections havehigh levels of neutralizing antibodies, particularly to thespike glycoprotein of the virus, which mediates host cell The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, whichpermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to theoriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit lineto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of thislicence, visit http://creat iveco mmons .org/licen ses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Hwang et al. J Hematol Oncol(2021) 14:38Page 2 of 11CD4 T cellCD8 T cellCD28B cellTCR antigenMHC ImRNA vaccineB7Protein vaccineBCRInactivated SARS-CoV-2or recombinant virus withSARS-CoV-2 antigenNucleusProfessionalAntigen Presenting CellPlasma cellAntibodyIMMUNE RESPONSEDNA vaccineVACCINE PLATFORMSFig. 1 Different types of COVID19 vaccines in development, mechanisms of antigen presentation, and generation of protective immunityattachment and viral entry [2]. Animal models indicatethat passive transfer of neutralizing antibodies are protective against SARS-CoV-2 infection [3, 4], and earlyadministration of convalescent plasma protects againstprogression of COVID-19 disease in human trials[5].However, antibodies are not sufficient, at least for clearing established disease, since high titers of neutralizingantibodies are found in patients with severe disease [6].In this regard, convalescent COVID-19 patients alsohave high levels of virus-specific T cells [7]. CD4 T-cellresponses appear to be at least as important as CD8 T-cell responses and recognize the spike protein amongothers [8, 9]. Neutralizing antibody, memory B and memory T cells specific to SARS-CoV-2 have now been foundin convalescent patients after six months [2, 10, 11]. Inaddition, one study identified a subset of individualswho rapidly resolved symptoms after being infected byCOVID-19 and found that they sustained both antibodyproduction and memory C D4 T-cells several monthsafter infection [9]. While immune correlates of protection have yet to be defined in humans, the data overallsupport that the integration of humoral and cell-mediated immunity to SARS-CoV-2 are the key to protectionand can be highly effective and durable.There are also immune responses that would beundesirable from a vaccine. In studies of SARS-CoV-1,immunization with inactivated virus provoked Th2mediated lung immunopathology upon infection [12,13]. This immunopathology was observed in animaldata and has not been observed for SARS-CoV-2 innon-human primate models [14, 15]. Nevertheless,investigators seek to minimize this risk by eliciting aTh1-skewed C D4 T-cell response. Another concernthat has been raised in the literature is that of antibodydependent enhancement (ADE) of disease, mediated byantibodies that bind to but do not neutralize the virus.ADE takes two main forms [16]. In one form, well characterized in dengue infections, virus is bound by antibody and the antibody-virus complex is internalized viainteractions with Fc gamma receptor into macrophageswhere it replicates. In the other form, non-neutralizingantibodies mediate the formation of immune complexes, which incite inflammation. ADE has been proposed as a concern for COVID-19 vaccine design dueto the finding of high levels of antibodies in severeCOVID-19 and in vitro observations that SARS-CoV-2is taken up by macrophages [16]. However, there areexplanations for high antibody levels in severe diseasesother than antibody-mediated harm, including chronicantigen stimulation and insufficiency of the antibodyresponse to clear established disease as describedabove. Importantly, SARS-CoV-2 does not productivelyreplicate in macrophages, making the macrophagemediated type of ADE less relevant. There is no compelling evidence of ADE from convalescent plasmatrials [5, 17, 18] or any of the human vaccine trials thusfar. Nevertheless, the likelihood of ADE is theoreticallydiminished by vaccines that focus the elicited antibodyresponse on neutralizing epitopes.

Hwang et al. J Hematol Oncol(2021) 14:38Page 3 of 11SARS‑CoV‑2 vaccines in use:At the time of writing, an astounding 66 COVID-19 vaccines are being tested in clinical trials, with 10 approvedfor at least limited use. Multiple platforms are represented among the leading candidates [19, 20], each withpros and cons (Table 1).Of note, aluminum adjuvants have been noted to initiate Th2 responses. In addition, ADE is theoretically morelikely with inactivated intact vaccines due to the inclusion of non-neutralizing epitopes. Nevertheless, therehave been no reports of ADE.Inactivated vaccinesSubunit vaccines contain an isolated protein of the target pathogen, produced recombinantly in cell culture andpurified (e.g., hepatitis B vaccine). Subunit vaccines circumvent dangers associated with introducing intact pathogen and the specific protein can be chosen to focus theimmune response on particular epitopes (e.g., neutralizing epitopes). Subunit vaccines stimulate C D4 T-celland antibody responses. However, since the protein isproduced ex vivo in cell culture, it may not retain nativepost-translational modifications or conformation. Inaddition, exogenous isolated proteins are not efficientlypresented via the pathways that stimulate cytotoxic Tcells, so subunit vaccines generally require adjuvants forimmunogenicity. NVX-CoV2373, developed by Novavax,contains full length spike protein produced from insectcells. In phase I/II trials [23], NVX-CoV2373 elicited highneutralizating antibody titers when delivered with adjuvant, exceeding titers in a panel of convalescent patients.Inactivated vaccines contain intact microbe that has beenkilled (e.g. the quadrivalent influenza vaccine). Inactivated vaccines present the entire virus and thus breadthof antigens to the immune system, but may requirean adjuvant to boost immunogenicity and are generally poor inducers of CD8 T cell immunity. Moreover,production of these vaccines is slow because it requireslarge-scale culture and inactivation. CoronaVac, a chemically inactivated vaccine by SinoVac, is provided in twodoses two weeks apart and uses aluminum adjuvant. Inphase I/II trials, it produced no serious adverse eventsand 90% seroconversion, but lower titers than in convalescent patients, and low T cell responses [21]. CoronaVac is licensed for limited use in China while phase IIItrials are underway. Sinopharm has developed two otherinactivated vaccines which induced humoral responses inhumans in Phase I/II studies [22] and are in limited use.Protein subunit vaccinesTable 1 Advantages and disadvantages of various types of COVID19 vaccines in developmentVaccine typeCOVID-19 vaccines furthestin ated virusSinoVac (CoronaVac aluminum)Entire virus, with all antigens presentedSinoPharm (Inactivated whole virus SARS- Prior experience and technology – e.g.,CoV-2 aluminum)quadrivalent influenza vaccineEasier storage – does not need to befrozenProtein subunitsNovavax (NVX-CoV2373)Vector Institute (EpiVacCorona)Can focus on antigens that generate neu- Produced ex vivo, may not retaintralizing antibodiespost-translational modifications orDoes not introduce intact pathogenconformationNot efficiently presentedLower humoral and cellular responseRequire adjuvants to boostReplication incompetent adenoviralvectorAstraZeneca (ChAdOx1 nCoV-19;AZD1222)Johnson & Johnson (Ad26.COV2.S)CanSino Biologics (Ad5-nCoV)Gamaleya (Sputnik V)Replication-defective, no new viralparticlesAvoids intact pathogenMimics natural infectionElicits humoral and cellular immunityAnti-vector immunity may interfereLower efficacy if prior anti-vectorimmunity existsDNAInovio (INO-4800)Mimic natural infectionElicits strong humoral and cellularimmunityAvoids introducing pathogenEasier to mass-produceDelivery into cell nucleusmRNAModerna (mRNA-1273)Pfizer-BioNTech (BNT162b2)Delivery into cytoplasmUnable to integrate into host genomeElicit strong humoral and cellularimmunityAvoids anti-vector immunityAvoids introducing pathogenEasier to mass-produceFragile – easily degradedNeeds lipid nanoparticle for deliveryFrozen for storageNeed adjuvants to boostPoor inducers of CD8 T-cell immunityHard to mass-produceLarge batches of live virus pose biosecurity risk

Hwang et al. J Hematol Oncol(2021) 14:38Th1-type CD4 T-cell responses were observed in mostparticipants. CD8 T-cell responses were not reported.No serious adverse events were noted, and reactogenicitywas generally mild to moderate, with fever in only 1 of 83vaccinated participants. Phase III trials are underway.Replication‑incompetent viral vectored vaccinesViral-vectored vaccines contain a delivery virus (e.g.,adenovirus) that has been recombinantly engineered tocontain genes encoding antigens of choice from the target pathogen. Upon inoculation, the engineered virusinfects host cells, leading to expression of the vaccineantigen. Often the recombinant virus is rendered replication-defective, so that host cells can be infected butcannot form new viral particles. Viral vector vaccinesavoid introduction of intact target pathogen and resultin endogenous antigen production mimicking naturalinfection, and thus are expected to elicit both humoraland cellular immunity. A disadvantage is that anti-vector immunity may interfere with prime-boost strategies or lead to low efficacy from preexisting anti-vectorimmunity.ChAdOx1 nCoV-19 (also known as AZD1222),developed by AstraZeneca, is a replication-deficientchimpanzee recombinant adenoviral vector vaccine containing the SARS-CoV-2 spike protein administered asa two-dose prime-boost regimen. The interim analysisof randomized controlled trials of ChAdOx1 nCoV-19found a vaccine efficacy of 62%-90% depending on dosing regimen and age [24, 25]. Of 10 participants hospitalized due to COVID-19 including one fatal case, all werein the control group. Reactogenicity was more commonwith the vaccine versus control. Serious adverse eventswere overall balanced between experimental and controlgroups, but did include a case of transverse myelitis following ChAdOx1 nCoV-19 booster vaccination. This caseled to a temporary pause in the phase II/III trial. The vaccine was eventually authorized for emergency use in theUK, Argentina, and India. Unlike the approved mRNAvaccines (see below), it is stable for months at refrigeration temperatures.Ad5-nCoV, produced by CanSino Biologics, is a replication-deficient adenovirus type-5 vectored vaccinecontaining full-length spike gene administered as a singledose [26]. Phase I studies showed good tolerability andimmunogenicity with induction of both specific T-celland humoral responses. However, the phase II study [27]showed induction of S-protein neutralizing antibodiesin only 47–59% of vaccinated participants, thought to bedue to preexisting immunity to adenovirus type 5. Thisvaccine has been approved for limited use in China.Ad26.COV2.S developed by Johnson & Johnson uses anon-replicating adenovirus-serotype 26 vector expressingPage 4 of 11full-length spike glycoprotein. A single dose elicitedstrong neutralizing antibodies and protection againstSARS-CoV-2 challenge in rhesus macaques [28]. PhaseI/IIa interim results [29] reported one vaccine-relatedserious adverse event (fever leading to hospitalization).There was a trend for overall higher reactogenicity withyounger age, including the occurrence of fevers in 19%of younger participants and 4% of older participants. Theseroconversion rate was 83–100% at day 29 by viral neutralization assays depending on dose and age of recipient.Cell-mediated responses were also observed: 80–83% ofpatients had Th1-skewed CD4 T-cell responses, and 51–64% had C D8 T cell responses. If approved, pending phase III trial results, Ad26.COV2.S would havethe advantages of potentially being administered as asingle-dose regimen and stable storage at refrigerationtemperatures.Other candidates include Sputnik V [30] developedby Gamaleya, which employs two different adenoviralvectors in a heterologous prime-boost strategy to circumvent anti-vector immunity to the prime. Phase I/IItrials reported elicitation of humoral and cell-mediatedresponses in all participants, without serious adverseevents. Sputnik V is in use in Russia with peer review ofphase III trial results pending.Nucleic acid vaccinesNucleic acid vaccines contain nucleic acids encoding aprotein antigen. Upon inoculation, the nucleic acids aretaken up by antigen presenting cells and expressed. Likeviral-delivered nucleic acids (i.e., viral vectored vaccines), nucleic acid vaccines mimic natural infection withendogenous antigen production and eliciting strong Tand B cell responses, while being entirely non-infectious.Making gene constructs at scale is more rapid than producing recombinant protein or inactivated pathogens,which is advantageous for vaccination against emergingvirus variants which has already been reported for SARSCoV-2 worldwide [31].Nucleic acid vaccine candidates include DNA plasmidvaccines and mRNA vaccines. A spike-protein expressingDNA vaccine was shown to elicit humoral and cellularimmunity in rhesus macaques [32]. Four DNA vaccinesare in at least phase II or III trials including Inovio’sINO-4800, with efficacy data in humans pending. mRNAvaccines have additional advantages over DNA andother vaccine platforms [33, 34]. mRNA is the normalintermediate between protein-encoding DNA and theproduction of protein in the cytoplasm. Thus whereasDNA vaccines need to be delivered into the cell nucleus,mRNA vaccines are delivered to the cytosol, avoidingrisk of host genome integration. mRNA is the minimalgenetic vector for translation of the antigen, avoiding

Hwang et al. J Hematol Oncol(2021) 14:38anti-vector immunity. Furthermore, mRNA is transient,degraded by ubiquitous RNAses and normal cellular processes. While mRNA vaccines had not previously beenlicensed for human use, they have been under development since the 1990s, including as cancer vaccinesencoding neoepitopes with early trials in patients withmelanoma. [35, 36]. Advancements in mRNA delivery,particularly lipid nanoparticle (LNP) technology enablingthe encapsulation and endosomal release of mRNA to thecytoplasm, have been key innovations that overcame initial concerns about the intrinsic fragility of mRNA andinefficient in vivo delivery [37]. Also key were discoveries of how to modulate the intrinsic immunogenicity ofmRNA using modified nucleosides [38]. By 2017, PhaseI trials had been performed of LNP-encapsulated mRNAvaccines against influenza, showing high seroconversionrates with an excellent safety profile [39].Both of the vaccines approved under emergency usein the United States – BNT162b2, developed by Pfizerand BioNTech, and mRNA-1273, developed by Moderna – are LNP-formulated, nucleoside-modified mRNAvaccines encoding the SARS-CoV-2 full-length spike protein modified by two proline mutations to lock it in prefusion conformation, given as a two-dose prime-boostregimen 21 days (for BNT162b2) or 28 days (for mRNA1273) apart.Phase I studies of BNT162b2 showed 100% anti-spikeseropositivity by day 21, boosted further by day 28 totiters above those of a COVID-19 human convalescentpanel [40]. A follow-up preprint [41] reported also expansion of spike-specific CD8 and Th1 subtype CD4 T cellresponses, with a high fraction producing interferon-γ. Inthe phase III trial, 43,548 participants were randomizedto two doses of BNT162b2 versus placebo, 37,706 ofwhom had sufficient follow up (median 2 months) [42].There were 162 cases of laboratory-confirmed symptomatic COVID-19 among 18,325 participants in theplacebo cohort, compared to 8 cases among 18,198 participants in the vaccinated cohort, yielding a vaccine efficacy of 95%. Efficacy was maintained ( 91%) across ageand underlying medical conditions. There were 10 casesof severe COVID-19, 9 in the placebo cohort and 1 in thevaccine cohort. Reactogenicity was frequent and mostlymild to moderate, with more than half of vaccinated participants experiencing fatigue and headaches, particularly after the second dose. Systemic adverse reactionsresolved in a median of 1 day and included fever in 16% ofyounger participants and 11% of older participants [43].Four patients out of 21,720 treated with at least one doseof vaccine developed Bell’s palsy at 3, 9, 37, and 48 daysafter vaccination and all resolved within 3 weeks (at 3,10, 15, and 21 days, respectively). [43] 8.8% had grade 3reactions (most common were fatigue, headache, musclePage 5 of 11pain, chills, and injection site pain) [40]. Few had severeadverse events (1.1% in BNT162b2 cohort, 0.6% in theplacebo cohort). Few had serious adverse events (0.6% vs0.5%), of which 1.6% (shoulder injury, lymphadenopathy)were considered by the FDA to be likely related to thevaccine [43].Phase I studies of mRNA-1273 showed 100% anti-spikeseropositivity in all dose groups, and S-specific Th1 subtype CD4 T-cell expansion. C D8 T cell responses weredetected at low levels. An updated analysis of the phaseI study reports durability of the humoral response, withtiters remaining above those of convalescent controls at90 days after second immunization [44]. In the phase IIItrial, 30,420 participants were randomized to mRNA1273 versus placebo. There were 185 cases of symptomatic COVID-19 infection in the placebo group and 11in the vaccinated group, yielding a vaccine efficacy of94.1% [45]. Efficacy was maintained ( 86%) across age,sex, race, and underlying medical conditions [46]. Therewere 30 cases of severe COVID-19, all in the placebogroup [46]. Reactogenicity was frequent, mostly mild tomoderate. Systemic adverse reactions resolved in a meanof 3 days. Grade 3 reactions occurred in 21.6% in themRNA-1273 recipients versus 4.4% in placebo. FourBell’s palsy cases were reported: 3 cases in 15,181 peopletreated in the vaccine group and 1 case in 15,170 peopletreated in the placebo group. These cases occurred at 22,27, 28, and 32 days after vaccination, with resolution in 3cases and one ongoing at the time of the FDA review. Fewhad serious adverse events (1.0% in vaccine recipientsversus 1.0% in placebo), of which 2.1% (nausea/vomiting,facial swelling) were considered by the FDA to be likelyrelated to vaccination [47].In sum, both mRNA vaccines offer highly effectiveprotection against symptomatic COVID-19 infection,mediated by a combined humoral and cell-mediatedimmune response with frequent reactogenicity but lowto no serious adverse effects. mRNA-1273 has a logisticaladvantage over BNT162b2, being stable at refrigerationtemperatures, compared to ultracold (-70 C) temperatures for BNT162b2.Implications for patients with cancerPatients 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 beendiagnosed with cancer in the last year and 16,570 werediagnosed with COVID-19, patients with cancer hadgreatly increased odds of COVID-19 infection (adjustedodds ratio (aOR) of 7; [52]). Odds of infection were highest for patients with recently diagnosed leukemia (aOR12.2), non-Hodgkin’s lymphoma (aOR 8.5), and lung cancer (aOR 7.7). Mortality is also higher in patients with

Hwang et al. J Hematol Oncol(2021) 14:38cancer who develop COVID-19: patients with cancerand 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 malignancyin the last 5 years, the increased risk of death has beenestimated to be at least 2.5-fold, and for other cancers, atleast 1.2-fold [48].Because of the increased vulnerability of patients withcancer to COVID-19 infections and mortality, there isurgent interest in vaccinating this population expeditiously. Considerations around expected safety and efficacy differ by therapy based on their general mechanismsand associated immune alterations.Considerations for patients treated with cytotoxicchemotherapiesCytotoxic chemotherapies interfere with DNA replication, synthesis, and cell cycle progression. Lymphocytesproliferate rapidly as part of activation and so are suppressed by these therapies [53]. However, suppression isnot complete and immune responses can nevertheless beelicited to vaccination while on cytotoxic chemotherapy.Patients with acute lymphoblastic leukemia, in which theimmune system is directly impacted by disease as well astreatment, can still generate immune responses after vaccination, ranging from 10 and 27% of patients immunizedwith hepatitis B and meningococcal subunit vaccines,respectively, to 100% of patients immunized with diphtheria and tetanus toxoid vaccines [54–56]. In studiesof responses to the annual inactivated influenza vaccinein patients with cancer, 10–42% of patients with hematologic malignancies responded to one dose of influenzavaccine [57–59], with additional responses with a second dose [57, 58]. Higher responses are seen in patientswith solid tumors on chemotherapy [60]: at least 78% inpatients with lung cancer [61] and 81% of patients withbreast cancer [59] on mild to moderately immunosuppressive regimens. When given between cycles of chemotherapy for lung or breast cancer, timing relative to thelast cycle may matter, though estimates of the optimalday varies [60, 62, 63]. Vaccination was well-toleratedin these studies. Infectious Diseases Society of America(IDSA) and The European Conference on Infections inLeukemia (ECIL) guidelines recommend yearly vaccination with inactivated influenza vaccine—an exceptionis during intensive therapy (e.g., induction and consolidation therapy for acute leukemias) given likely poorresponse, but considered reasonable given seasonalnature of influenza [64, 65]. Hepatitis B subunit andpneumococcus vaccinations may also be recommendedeven during chemotherapy [65, 66]. Titers can be helpful to assess need for revaccination [64, 66]. Higher dosesPage 6 of 11or boosters are employed to enhance immunogenicity toinactivated influenza, pneumococcal polysaccharide, andhepatitis B subunit vaccines [64–66]. Overall, with theexception 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 therapiesTargeted therapies include receptor tyrosine kinaseinhibitors (TKIs) such as erlotinib, sunitinib, and imatinibor monoclonal antibodies such as trastuzumab. Targetedtherapies should not directly cause immunosuppression as part of their mechanism of action, but may haveunintended inhibitory effects on antigen presenting cellfunction, T cell activation [67] and B cell signaling [68].Nevertheless, patients treated with sunitinib or sorafenibdevelop seroprotection with the influenza vaccine comparable to healthy controls [69]. Similarly, patients withchronic myelogenous leukemia (CML) on TKIs developseroprotection after the influenza vaccine at reduced butstill substantial rates around 40% [68]. There was also nodifference in seroprotection against influenza when comparing controls versus patients with breast cancer treatedwith 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 afterinfluenza vaccination [71, 72], though 75% of patients onibrutinib were able to respond to subunit vaccines againstvaricella zoster [73]. The ECIL group recommends thatpatients with CML on TKIs receive the yearly inactivatedinfluenza vaccine and to be vaccinated against Streptococcus pneumoniae. Thus, it is reasonable to expect thatpatients being treated with targeted therapies will generate protective responses with COVID-19 vaccination.Considerations for patients treated with immunecheckpoint inhibitorsImmune 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 endogenousanti-tumor activity. While cancers such as lung cancersand comorbidities such as smoking have been associatedwith higher severity of COVID-19 infections [50, 74, 75],concurrent immune checkpoint inhibitor treatments forpatients with lung cancer have not been associated withmore severe infections or mortality when adjusted forsmoking status [76].Checkpoint inhibitors incur a risk of immune-relatedadverse events (IRAEs), at a rate of 17–48% for any

Hwang et al. J Hematol Oncol(2021) 14:38Page 7 of 11grade and 5–8% severe grade, depending on the specific therapy [77]. There is a theoretical concern thatvaccination could stimulate an overexuberant immuneresponse and increase IRAEs in patients actively treatedwith immune checkpoint inhibitors. A 2018 study of 23patients on immune checkpoint inhibitors who receivedthe influenza vaccine found a high rate of IRAEs (52%).However, subsequent larger studies including three withnon-vaccinated comparison groups did not show higherfrequencies of IRAEs with vaccination [78, 79]. Moreover, immune checkpoint inhibitors are considered safe touse 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 seroprotectionis generally not substantially diminished [78, 80]. Thus,we expect that patients on immune checkpoint inhibitortherapy should make protective responses with COVID19 vaccin

Protective immunity against viral infections involves humoral immunity and cell-mediated immunity (Fig. 1). Humoral immunity is provided by B lymphocytes which produce antibodies which may neutralize virus by bind-ing virus and preventing its entry into host cells. Cell-mediated immunity includes macrophages and CD8 sues. Productive T cell .

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