The effect of COVID-19 on cancer immunotherapy and cancer care

Introduction

The world of cancer care continues to be significantly affected by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2; coronavirus disease 2019 [COVID-19]) global pandemic. COVID-19 has demonstrated unprecedented transmissibility as a highly infectious RNA respiratory virus causing serious morbidity and mortality. On March 11, 2020, the World Health Organization declared COVID-19 a global pandemic. Health care systems everywhere were quickly overwhelmed as they were called upon to provide hospitalization for a sudden tremendous surge in COVID-19-infected patients. Hospitalized patients with COVID-19 often required intensive care (ICU) beds and ventilator support for severe respiratory distress. As expected, it was quickly observed that individuals with malignant disease were at a higher risk for COVID-19 infection and for having greater disease severity and mortality. The tremendous effect of the pandemic on health care systems and health care workers immediately caused disruptions to the delivery of normal cancer care, both anticancer therapy and cancer screening. Patients with cancer frequently delayed or abandoned active treatment out of fear of becoming infected if they were to actually go to their point of care. ^,

Stressed hospitals were forced to delay surgical procedures. Cancer clinical trials were severally limited or even placed on hold as staff had to be shifted to COVID-19 patient care and research support staff was transferred to remote work. At major academic centers, clinical investigators were called upon to urgently shift their focus to COVID-19 research. At Johns Hopkins, a special COVID-19 Institutional Review Board (IRB) was established and throughout the remainder of 2020 and 2021 met every day of the week to expedite proposed COVID-19 research protocol reviews. By the end of 2020, there was a glimmer of hope, as safety and efficacy data generated by large-scale clinical trials of several candidate vaccines received U.S. Food and Drug Administration (FDA) review and emergency use authorization (EUA) in the United States as well as review and similar approval in other countries.

Over the months since the introduction of the vaccines and priority access to vaccination for patients with cancer, cancer care, cancer research, and cancer screening have gradually begun to return to prepandemic status. Even with the current much lower incidence of infections in the population, it will take some time to completely understand the true disruption that COVID-19 has had on the incidence and mortality caused by cancer. Though the vaccines have had a major effect, it is important to recognize that the pandemic continues. On March 10, 2022, the Johns Hopkins Coronavirus Resource Center website reported that the number of global COVID-19 documented cases for the previous 28 days was 48,132,252, with 242,345 deaths. In the United States the 28-day total cases were 2,107,247 and there were 49,440 deaths. The total number of individuals documented as dying from COVID-19 in the United States since the beginning of the outbreak had reached 965,069. Many believe this to be a significant underestimation.

During the 2 years since January 2020, much has been learned about this specific coronavirus, and much knowledge has been gained regarding the public health management of a serious viral pandemic. Though there exists considerable knowledge regarding the innate and adaptive immune responses and the heterogeneity of those responses to tumors of different organ sites and histologies, there is still much to learn regarding the effect of COVID-19 infection on the existing anticancer immune response and on the timing of cancer therapies, especially immunotherapy. Such knowledge regarding COVID-19’s effect on cancer immune therapies is aided to some degree by previous experience in many patients with cancer harboring other chronic infections such as human immunodeficiency virus (HIV), human papillomavirus (HPV), hepatitis B, and hepatitis C. This chapter will attempt to summarize what we currently know regarding COVID-19 and to do so in the context of malignancy and anticancer immune therapy.

The emergence and global effect of SARS-CoV-2

In early December 2019, there was increasing awareness regarding an outbreak of a serious and novel life-threating acute respiratory viral illness spreading in and around the city of Wuhan in the Hubei Province of China. The exact origin of this virus has been an ongoing debate, with considerable difficulty encountered by epidemiologists in exercising a full-force investigation. The early cases of the severe respiratory illness were said to be related to an open-air market located in Wuhan, China. By January 26, 2020, there were 2794 laboratory-confirmed cases resulting in 80 deaths and evidence documenting the beginnings of global spread to at least 33 individuals in 10 countries.

A complete genome sequence of isolates from hospitalized patients documented the causative agent to be an RNA coronavirus virus. The complete sequence was initially obtained by scientists at the Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China. The initial sequence and subsequent analysis was based on specimens obtained from seven severely ill hospitalized patients in Wuhan and showed that the novel disease-causing virus was 96% identical to a bat coronavirus and shared 79.6% sequence identity with viruses known to cause SARS. ^, Coronaviruses have previously been determined to cause SARS and Middle East respiratory syndrome (MERS).

Spread of the COVID-19 respiratory virus is mainly through person-to-person contact and the inhalation of microdroplets and aerosols containing viral particles. This occurs when an infected person coughs, sneezes, or simply talks during direct person-to-person contact. Less common modes of spread include a fecal–oral route, leading to identification of the virus in site-specific sewage and in wastewater at municipal treatment plants. There has been evidence in a small percentage of cases of vertical maternal transmission to the newborn especially occurring during late stages of pregnancy.

SARS-CoV-2 causes nasopharyngeal and lower respiratory tract infections. Most infections appear to be mild, and though it is difficult to be certain, somewhere between 20% and 40% of those infected are asymptomatic or only mildly symptomatic. However, for a great number of patients the disease is much more severe, leading to hospitalization and acute respiratory distress syndrome (ARDS). Patients requiring hospitalization can present with a severe interstitial pneumonia, sometimes further complicated by systemic inflammation, thromboembolic events, evidence of cardiac complications, and massive cytokine release. ^{, ,} Currently recognized risks for severe disease requiring hospitalization include lack of complete vaccination and medical comorbidities such as immunodeficiency, obesity, cardiopulmonary diseases, and cancer. During the beginning of the pandemic, the risk of COVID-19 infection was estimated to be seven times greater for the patient with cancer and even greater for the non-White population of patients with cancer. ^,

COVID-19 rapidly became a pandemic, putting extreme pressure on health care workers and the infrastructure of health care systems. Despite well-proven public health measures required to manage a global pandemic caused by a rapidly spreading respiratory virus, the attempted implementation of these measures in the United States became a major political challenge. This unfortunate turn of events and the lack of our medical system’s preparedness for such an occurrence will certainly be the subject of debate for many years to come. At the time of this writing, we are improving from the latest wave of COVID-19, Omicron BA.1, but by no means are we able to declare that the pandemic is behind us as Omicron BA.2 begins to spread in the United States ( https://coronavirus.jhu.edu/map.html , accessed March 10, 2022). We must continue to be vigilant, increase the rate of maximum vaccination, increase the ease and availability of testing, and, above all, significantly enhance our genetic surveillance searching for new viral variants. One important lesson to be learned from our experience attempting to manage this global pandemic is the tremendous need for public education regarding the very basics of infectious disease and the methodologies of sound public health to minimize the effect of future pandemics.

The vast global and extremely rapid spread of COVID-19 provides significant opportunities for the occurrence of viral mutations as the virus replicates within the host’s cells, producing new variants of the virus. The world has already experienced the challenges of several of these new variants of the original COVID-19, namely, Delta and Omicron BA.1 and BA.2. ^, The U.S. government through the Centers for Disease Control and Prevention (CDC) has significantly increased its approach to population sampling and virus sequencing in an effort to stay ahead of the development of new COVID-19 variants circulating in the population. The CDC has established a classification process for new COVID-19 variants that places newly identified viral variants into one of three groups: variants of interest, variants of concern, and variants of high consequence (for in-depth review, see Xu et al. ).

SARS-CoV-2 structure and biology

SARS-CoV-2 (COVID-19) is an enveloped, single-stranded RNA virus and has proved to cause an extremely infectious and severe respiratory illness with clinical features of fever, cough, dyspnea, malaise, severe rapidly progressing interstitial pneumonia, and acute respiratory distress syndrome (ARDS). SARS-CoV, MERS-CoV, and COVID-19 all belong to the β-CoV genera, one of the four described Coronaviridae genera. ^, Currently the β-CoV subgroup is recognized as having the highest human mortality rates among the four coronavirus genera. ^{, ,}

Structurally, COVID-19 is composed of four major proteins: the spike protein (S); the nucleocapsid protein (N); the membrane protein (M), which has a short N-terminal ectodomain with a cytoplasmic tail; and the hydrophobic envelope protein (E). ^, The nucleocapsid protein (N) is complexed with the genomic RNA to form a helical capsid. The spike or S protein is a type 1 glycoprotein that forms peplomers on the virus surface. The RNA virus has several open reading frames (ORFs) encoding accessory proteins ( Fig. 13.1 ).

The respiratory tract is the primary site for viral particle entry in humans. The main transmission of the virus occurs in the form of COVID-19 encapsulated virus particle aerosols and microdroplets released by infected hosts. For the virus to survive and replicate, it must enter into host cells. ^, This occurs via the S1 subunit of the spike protein on the virus surface that recognizes and binds to the human angiotensin-converting enzyme-2 (hACE-2) receptor expressed on respiratory tract cells, vascular endothelium, cardiovascular tissue, renal tissues, and intestinal epithelium. ^{, ,} The normal function of ACE2 is to convert angiotensin II to angiotensin-(1-7). A serine protease, TMPRSS2, is also involved and acts to prime the S protein for ACE2 binding and host cell entry.

The host cell entry process is assisted by other proteins including neurophilin-1, heparin sulfate proteoglycans, and C-type lectins. In the infected cell cytoplasm, the viral RNA is translated into two polyproteins pp1a and pp1ab and 16 nonstructural proteins that function to form the viral replication–transcription complex generating an antisense negative-strand template of the viral RNA. Double-membrane vesicles formed from membranes of the endoplasmic reticulum (ER) and the Golgi compartmentalize and isolate within the cytoplasm the process of viral replication. The assembly of new viral particles within the ER–Golgi compartment generates virion-containing vesicles that fuse with the host cell plasma membrane for exocytosis and release of the virus into the extracellular space. ^, From these several steps in the pathologic process of viral infection and replication, there are numerous opportunities for the virus to be recognized as nonself, to initiate a host inflammatory response, and to first activate the innate immune response, followed quickly by the more critical adaptive immune system response ( Fig. 13.2 ) (for in-depth review, see Diamond and Kanneganti ).

The angiotensin-converting enzyme 2, SARS-CoV-2 infection, and cancer

Angiotensin-converting enzyme 2 (ACE2) is the cell surface receptor required for SARS-CoV-2 entrance into the host cells. ^{, ,} As expected, studies quantitating the expression of ACE2 in various tissues correlate both the risk of becoming infected and the severity of the viral infection. ^{, ,} Ren and colleagues reported studies early in the pandemic (March 2020) focused on determining the level of ACE2 expression in normal patient tissues and in tissues of patients with cancer. Their studies using primarily the Gene Expression Profiling Interactive Analysis (GEPIA) database and ONCOMINE to compare mRNA expression of ACE2 in tissues found that the kidneys, duodenum, intestine, gallbladder, and testis had the highest level of ACE2 expression. The colon, rectum, and seminal vesicles displayed a moderate level of expression, with the lungs having the lowest expression.

ACE2 is recognized to have a significant role in cancer prognosis, demonstrating a protective anticancer effect. In these studies, ACE2 expression was upregulated in renal cancer, gastrointestinal tumors, and lung cancer. Other studies of malignant tumors and cancer cell lines suggest that essentially all cancer tissues can express ACE2. Studies indicated that ACE2 is overexpressed in colon adenocarcinoma, renal papillary cell carcinoma, pancreatic adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, and lung adenocarcinoma. ^{, , ,}

In patients with cancer infected with COVID-19, there is evidence that the promotor for ACE2 expression is hypomethylated but not to the degree that it is in non-COVID-19-infected patients with cancer. ^, Studies documenting the importance of the level of ACE2 expression in patients with cancer demonstrate that upregulation of ACE2 in multiple cancer types is associated with suppression of multiple oncogenic pathways, including cell cycle proteins, vascular endothelial growth factor (VEGF), transforming growth factor beta (TGF-β), and the Wnt and Notch signaling pathways. Increased levels of ACE2 in cancer are also directly correlated with enhancement of an antitumor immune response. Taken together, ACE2 upregulation results in enhanced disease prognosis. More specific to the use of immunotherapies in cancer, ACE2 expression has been shown to directly correlate with expression of programmed death ligand 1 (PD-L1) in patients with cancer. Tumors express PD-L1 to varying degrees, which binds to T cells, causing immunosuppression of the antitumor immune response and tumor progression.