Longitudinal Analyses of COVID-19 Vaccination in Patients With Lung Cancer: Antibody Responses and Variant-Specific Neutralization

Declared a pandemic in March 2020, the COVID-19 infection disseminated with a swiftness and severity unprecedented in modern times. Doctors and health care workers from multiple specialties, including those in oncology, were called to the frontlines to confront this new disease. For the thoracic oncology community, three fundamental questions immediately arose: how would infection with SARS-CoV-2 affect the treatment and progression of lung cancer; how would a diagnosis of lung cancer interact with and potentially exacerbate COVID-19 infection; and of course, how do we provide appropriate diagnosis, staging, and complex treatment/follow-up regimens during the pandemic? These overarching questions do not do justice to the underlying complexity inherent in the collision of these two diseases. Unknown at the time, and still in question today, are issues concerning cellular biology, immunology, inflammation, treatment planning, comorbidities, and risk management across disparate members of the lung cancer patient community.

THE TAKEAWAY

• In the article accompanying this editorial, Valanparambil et al⁶ performed longitudinal studies of anti–severe acute respiratory syndrome coronavirus 2 SPIKE protein titers and the ability of these antibodies to neutralize authentic virus in patients with lung cancer after vaccination and boost with a mRNA vaccine and although 75% of patients mounted a good anti-viral immune response, 25% failed to generate an adequate immune response after initial vaccination, raising questions about causes of this failure and optimal approaches to vaccinate patients with lung cancer. This study indicates both the need to monitor our patients with lung cancer for response to COVID-19 mRNA vaccines, identify the nonresponders for follow-up and further attempts at immunization, and continue collecting and analyzing clinicodemographic information and biospecimens from our patients.

We are proud to say, thoracic oncology researchers at multiple academic centers as well as private practices including clinical and laboratory investigators, patient advocates, patients and their families, and federal agencies including the National Cancer Institute and their Program Staff were quick to rally to these considerable challenges. Early reports indicated that patients with lung cancer appeared to be at particularly high risk of accelerated mortality, with a case fatality rate of 25%-40% reported in several global publications.^1-5 Research groups and government agencies set about developing and implementing longitudinal studies to monitor the impact of SARS-CoV-2 infection on patients with lung cancer, even while trying to understand and mitigate logistic issues resulting in delays in diagnoses and treatment. In December of 2020, well ahead of their anticipated schedules, vaccines were approved across multiple countries. This raised a new question: what is the impact of lung cancer in individual patients along with related clinical demographics (eg, stage, histology, and molecular characteristics) and its treatment, on the immune response to SARS-CoV-2 vaccination? As the pandemic evolved, so did the ongoing studies, adapting to provide answers to a complex series of emerging questions related to maintenance of antibody titers over time in patients with cancer, the role of cellular immunity, and the impact of novel SARS-CoV-2 variants of concern, including Omicron.

An important study starting to fill these knowledge gaps is presented in the article that accompanies this editorial by Valanparambil et al.⁶ In this report with state-of-the-art analyses of antibody titers and neutralization ability in 83 patients with non–small-cell lung cancer (NSCLC) compared with 53 healthy volunteers, the authors observed a sizable subset (25%) of patients with lung cancer who exhibited significantly compromised anti–SARS-CoV-2 SPIKE protein antibody binding ability in response to mRNA-based vaccines.⁶ Importantly, they also tested for the ability of antibodies from these patients to neutralize the infection of live virus in cell assays—a crucial determinant of potential effectiveness. In this case, they found that 18% of patients with lung cancer failed to mount detectable neutralization, seven-fold lower than what they found in their control population. In addition, they found a highly significant correlation (r values of approximately 0.8) between anti-SPIKE, anti-viral receptor-binding domain titers, and viral neutralizing titers. How general are these results? It was reassuring to see their findings are in line with other recent reports that observe a similar subset of patients with deficient immune responses compared with control populations. In our own studies conducted at the same time, we found a 5% subset of 114 patients with NSCLC in whom antibody titers were undetectable (measured at zero) despite full courses of mRNA vaccines, a phenomenon not observed in our controls despite age-matching.⁷ Other pan-cancer studies have reported similar results, including the CANVAX study, which evaluated more than 750 patients with cancer, also identifying a subset with substantially diminished antibody levels and neutralization activity.⁸ Although the CANVAX study included 193 patients with lung cancer, their publication analyzed all patients with solid tumors as a group and only baseline vaccine responses were reported. These other studies have also shown that characteristics not atypical to patients with lung cancer, such as advanced age or active smoking, are associated with low immunization rates^9-11; thus, selection of appropriate control populations is essential.

The emergent and still-evolving Omicron variants of SARS-CoV-2 that harbor the capacity to breakthrough initial vaccination-induced immunity raises significant new concerns for patients with lung cancer. Although it has been shown that third mRNA vaccine doses increase Omicron antibody neutralization in the general population,^12-14 the efficacy of this third dose specifically in patients with lung cancer is a key question presently being addressed. Thus, it was very good news to see in the report by Valanparambil et al⁶ that a third (booster) vaccination resulted in highly significant increases in antibody binding titers to both ancestral (wild-type) and Omicron SARS-CoV-2 variants, albeit with Omicron binding still significantly lower than wild-type. Nevertheless, they point out that neutralizing antibody titers again Omicron were significantly diminished compared to the wild-type strain in patients with lung cancer, with 6 of 10 patients with NSCLC failing to maintain detectable titers over a short period of time. Similarly, we found a 21% failure to detect Omicron neutralization antibody titers after booster vaccination.⁷ Most of us were surprised by the finding that there was no obvious clinicodemographic and treatment relationship with lack of ability to mount an immune antibody response after vaccination. Clearly, more information is needed on this key issue, including prospective studies that will analyze larger numbers of patients from multiple institutions and treatment venues.

How do we use this information to help our patients? Obviously, we tell our patients to get vaccinated and boosted, and since the majority of the information is from mRNA vaccines, we recommend use of one of the mRNA vaccines. Since there are no clear clinicodemographic data, all patients with lung cancer should be treated, in regard to SARS-CoV-2 immunization, in the same manner irrespective of age, sex, stage, smoking status, histology, oncogenotype, or treatment. How do we integrate vaccination into lung cancer treatment regimens, particularly chemotherapy with its known immunosuppressive effects? At this point, we simply do not know and we need to have more information to determine whether patients are best served by delaying or reducing lung cancer treatment for some period surrounding vaccination. The studies to date have focused on humoral immune responses, and we know that cellular immunity against SARS-CoV-2 will also be important. Thus, we await ongoing studies of cellular immune responses to vaccines in patients with lung cancer. The studies to date have focused largely on NSCLC and we urgently need data on vaccine responses in small-cell lung cancer as well. Given the identification of a significant subset of patients with lung cancer who fail to mount an adequate immune response, the waning of antibody levels over time, and the high correlation between antiviral binding titers and antibody neutralization titers, it would seem prudent to serially follow anti-SPIKE antibody titers in our patients. If they mount and maintain significant levels, then it is reasonable to proceed with their management of COVID-19 infection in the same manner as other individuals of their age. Such antibody titers are now becoming widely available as Clinical Laboratory Improvement Amendments–certified tests. However, if patients fail to develop antibody titers or these wane rapidly to undetectable levels, it would be important to have them receive additional booster vaccinations or potentially therapeutic antibodies such as tixagevimab copackaged with cilgavimab. Clearly, we will need prospective studies of such patients. Current findings also highlight the need to develop broader databases with results from a representative cross-section of individual patients, particularly longitudinal titer measurements, so we can evaluate information on much larger numbers of patients from multiple demographics and treatment venues. As new information emerges, it will be important to develop evidence-based guidelines as now routinely available for cancer treatments. Finally, we note that since lung epithelial cells are the usual primary site of SARS-CoV-2 infection and replication including cytokine release, it will be important to know if this infection affects the risk of developing lung cancer and the type or characteristics of lung cancer that develops in a person who previously had COVID-19 infection.

AUTHOR CONTRIBUTIONS

Conception and design: All authors

Financial support: John D. Minna

Collection and assembly of data: Philip C. Mack, Paul A. Bunn, John D. Minna

Data analysis and interpretation: Philip C. Mack, Fred R. Hirsch, John D. Minna

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Longitudinal Analyses of COVID-19 Vaccination in Patients With Lung Cancer: Antibody Responses and Variant-Specific Neutralization

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