Cure Alveolar Soft Part Sarcoma International (iCureASPS)

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Corona virus disease-19 pandemic & cancer patients

On 11 March, the WHO formally declared the corona virus disease-19 (COVID-19) outbreak a pandemic [1]. After the first cluster of cases emerged from Wuhan, in China, at the end of 2019, up today almost 287000 cases of infections from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been diagnosed across all five continents in the last few months [2,3].

COVID-19 morbidity and mortality have been linked to elderly age and comorbidities, leading to a poorer outcome to the viral infection for frail patients and more often resulting in hospitalization, intensive care unit admittance and need for invasive tracheal intubation [4]. Among such individuals, cancer patients represent a large subgroup at high risk of developing coronavirus infection and its severe complications. A recent nationwide analysis in China demonstrated that, of 1590 COVID-19 cases from 575 hospitals, 18 had a history of cancer (1 vs 0.29% of cancer incidence in the overall Chinese population, respectively), with lung cancer as the most frequent diagnosis [5]. Patients with cancer were observed to have a higher risk of severe events compared with patients without cancer (39 vs 8%; p = 0.0003). Moreover, cancer patients who underwent recent chemotherapy or surgery had a higher risk of clinically severe events than did those not receiving treatment. With the limit of a small sample size, the authors concluded that patients with cancer might have a higher risk of COVID-19, and poorer outcomes, than individuals without cancer. As a consequence, they recommended to consider an intentional postponing of adjuvant chemotherapy or elective surgery for stable cancer in endemic areas [5].

Nevertheless, as subsequently highlighted by other authors, the true incidence of COVID-19 in patients with cancer would be more informative in assessing whether such patients have an increased risk (and morbidity) from this viral illness [6]. Furthermore, the limited cancer patient population described in this first report from the literature, was curiously characterized by the lack of individuals receiving anticancer immunotherapy. Indeed, only chemotherapy and surgery were cited among treatments received by patients in the month prior to developing COVID-19. Maybe, this could simply be due to the casualty of a small sample, or otherwise, it could suggest that cancer patients receiving immunotherapy are less prone to develop COVID-19 or to be admitted in hospital due to severe coronavirus symptoms. Currently, we are aware of the probably higher incidence of misdiagnosed coronavirus infections compared with that reported and updated every day; it is likely that a great portion of healthy and young population develop COVID-19 with mild symptoms, not requiring hospital admittance and thus escaping the laboratory confirmation of the disease [7]. Cancer patients undergoing treatment with anti-PD-1/PD-L1 or anti-CTLA-4 immune checkpoint inhibitors (ICI) currently used in everyday practice to treat solid tumors such as melanoma, lung cancer, renal carcinoma, urothelial cancers and head and neck carcinoma constitute a growing oncological population [8]. Their specific susceptibility to bacterial or viral infections has not been investigated. Considering that immunotherapy with ICI is able to restore the cellular immunocompetence, as we previously suggested in the context of influenza infection, the patient undergoing immune checkpoint blockade could be more immunocompetent than cancer patients undergoing chemotherapy [9,10].”


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117596/

“Potential interference between COVID-19 pathogenesis & immune checkpoint blockade

In the recent weeks, in the countries heavily interested by the COVID-19 outbreak, such as Italy, the scientific associations recommended the prudential postponing of active cancer treatments, especially for stable patients not needing urgent interventions [11]. On one hand, this recommendation could be reasonable for advanced cancer patients receiving chemotherapy, with the risk of hematological toxicity and of worsening an immunosuppressed status, thus favoring COVID-19 morbidity [5]. On the other hand, some oncologists are even currently wondering about the risk of administering ICI in the middle of the COVID-19 outbreak, essentially due to two major concerns.

The first seems to be represented by the potential overlap between the coronavirus-related interstitial pneumonia and the possible pneumological toxicity from anti-PD-1/PD-L1 agents. Even if lung toxicity is not the most frequent adverse event of ICI, it can be life threatening. The overall incidence rate of ICI-related pneumonitis ranges from 2.5–5% with anti-PD-1/PD-L1 monotherapy to 7–10% with anti-CTLA-4/anti-PD-1 combination therapy [12]. The dominant radiological pattern of lung immune-related adverse events (irAEs) is organizing pneumonia, but ICI-related pneumonitis could exhibit a variety of patterns, also including nonspecific interstitial pneumonitis [13]. Despite being rarer than other irAEs, pneumonitis is the most fatal AE associated with PD-1/PD-L1 inhibitor therapy, accounting for 35% of treatment-related toxic deaths [14]. Considering that underlying lung disease, particularly including interstitial pneumopathy, is considered a risk factor for ICI-related pneumonitis, it could be reasonable taking into account the risk of treating patients while they are developing an initial form of COVID-19. The synergy between the two lung injuries, despite only hypothetical, cannot be surely ruled out. Nevertheless, such an epidemiological coincidence should not prevent the oncologist from offering a potentially effective and often well-tolerated treatment even in the middle of the COVID-19 outbreak, since the duration of the pandemic is still currently unpredictable. This is true in particular considering the potentially curative aim of ICI treatment in the context of highly responsive diseases, such as melanoma and renal cell carcinoma and in the adjuvant setting even more than in the advanced disease.”

“The second concern seems to be represented by a possible negative interference of ICI in the pathogenesis of COVID-19. Cytokine-release syndrome (CRS) is a phenomenon of immune hyperactivation typically described in the setting of T cell-engaging immunotherapy, including CAR-T cell therapy but also anti-PD-1 agents [15]. CRS is characterized by elevated levels of IL-6, IFN- γ and other cytokines, provoking consequences and symptoms related to immune activation, ranging from fever, malaise and myalgias to severe organ toxicity, lung failure and death. In parallel, one of the most important mechanism underlying the deterioration of disease in COVID-19 is represented by the cytokine storm, leading to acute respiratory distress syndrome or even multiple organ failure [16]. The cytometric analyses of COVID-19 patients showed reduced counts of peripheral CD4 and CD8 T cells, while their status was hyperactivated. In addition, an increased concentration of highly proinflammatory CCR6+ Th17 in CD4 T cells has been reported, and CD8 T cells were found to harbor high concentrations of cytotoxic granules, suggesting that overactivation of T cells tends to contribute to the severe immune injury of the disease [17]. Moreover, the pathological findings associated with acute respiratory distress syndrome in COVID-19 showed abundant interstitial mononuclear inflammatory infiltrate in the lungs, dominated by lymphocytes, once again implying that the immune hyperactivation mechanisms are at least partially accountable for COVID-19 severity [17]. Considering these aspects, the hypothesis of a synergy between ICI mechanisms and COVID-19 pathogenesis, both contributing to a counter-producing immune hyperactivation, cannot be excluded.”

“Conclusion

Clinical decisions about cancer patients deserving immunotherapy in the current context of the COVID-19 pandemic should be characterized by separated reflections, avoiding generalizations and remembering their deeply different immunological status compared with that of cancer patients undergoing chemotherapy or targeted agents. In the end, beyond any charming scientific speculations, it is unfortunately likely that in this COVID-19 pandemic, the greatest risk for cancer patients is the unavailability of the usually high-level medical services, since all our hospital resources, in terms of structures, tools and healthcare professionals, are currently strongly dedicated to the outbreak management.”

Background: The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed great threat to human health. T cells play a critical role in antiviral immunity but their numbers and functional state in COVID-19 patients remain largely unclear.

Methods: We retrospectively reviewed the counts of T cells and serum cytokine concentration from data of 522 patients with laboratory-confirmed COVID-19 and 40 healthy controls. In addition, the expression of T cell exhaustion markers were measured in 14 COVID-19 cases.

Results: The number of total T cells, CD4+ and CD8+ T cells were dramatically reduced in COVID-19 patients, especially in patients requiring Intensive Care Unit (ICU) care. Counts of total T cells, CD8+ T cells or CD4+ T cells lower than 800, 300, or 400/μL, respectively, were negatively correlated with patient survival. T cell numbers were negatively correlated to serum IL-6, IL-10, and TNF-α concentration, with patients in the disease resolution period showing reduced IL-6, IL-10, and TNF-α concentrations and restored T cell counts. T cells from COVID-19 patients had significantly higher levels of the exhausted marker PD-1. Increasing PD-1 and Tim-3 expression on T cells was seen as patients progressed from prodromal to overtly symptomatic stages.

Conclusions: T cell counts are reduced significantly in COVID-19 patients, and the surviving T cells appear functionally exhausted. Non-ICU patients with total T cells counts lower than 800/μL may still require urgent intervention, even in the immediate absence of more severe symptoms due to a high risk for further deterioration in condition.



https://www.frontiersin.org/articles/10 ... exhaustion

Discussion
T cells play a vital role in viral clearance, with CD8+ cytotoxic T cells (CTLs) capable of secreting an array of molecules such as perforin, granzymes, and IFN-γ to eradicate viruses from the host (13). At the same time, CD4+ helper T cells (Th) can assist cytotoxic T cells and B cells and enhance their ability to clear pathogen (14). However, persistent stimulation by the virus may induce T cell exhaustion, leading to loss of cytokine production and reduced function (15, 16). Earlier studies have been unclear regarding the numbers and function of T cells in COVID-19 patients, albeit with suggestions of depressed lymphocyte counts (4, 6). In this report, we retrospectively reviewed the numbers of total T cells, CD4+, CD8+ T cell subsets in a total of 499 COVID-19 patients. In Non-ICU patients, we found that over 70.56% cases had a decrease in total, CD4+ and CD8+ T cells. However, in the ICU group, a total of 95% (19/20) patients showed a decrease in both total T cells and CD4+ T cells, and most importantly, all of the patients displayed decreases in CD8+ T cells. We also analyzed Non-ICU patients in greater detail, and found that urgent intervention may be necessary to preempt the development of severe symptoms in patients with low T cell counts.

Cytokine storm is a phenomenon of excessive inflammatory reaction in which cytokines are rapidly produced in large amount in response to microbial infection. This phenomenon has been considered an important contributor to acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS) (17, 18). It has been also implicated in the setting of respiratory viral infections, such as SARS in 2002, avian H5N1 influenza virus infection in 2005 and H7N9 infection in 2013 (19–22). Huang et al. showed that the levels of IL-2, IL-7, IL-10, TNF-α, G-CSF, IP-10, MCP-1, and MIP-1A were significantly higher in COVID-19 patients (4). Consistent with this report, here we found that the secretion of cytokines including TNF-α, IL-6, and IL-10 was increased in COVID-19 patients. Interestingly, the numbers of total T cells, CD4+ T and CD8+ T cells are negatively correlated to levels of TNF-α, IL-6, and IL-10, respectively (Figure 2B), suggesting these cytokines may be involved in the decrease of T cells detected in COVID-19.

TNF-α is a pro-inflammatory cytokine which can promote T cell apoptosis via interacting with its receptor, TNFR1, which expression is increased in aged T cells (23, 24). Our current analysis demonstrated that patients over 60 years old have lower T cell numbers, indicating that TNF-α might be directly involved in inducing T cell loss in these patients. IL-6, when promptly and transiently produced in response to infections and tissue injuries, contributes to host defense through the stimulation of acute phase responses or immune reactions. Dysregulated and continual synthesis of IL-6 has been shown to play a pathological role in chronic inflammation and infection (25, 26). Tocilizumab, a humanized anti-IL-6 receptor antibody, has been developed and approved for the treatment of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (27, 28). Moreover, tocilizumab has been shown to be effective against cytokine release syndrome resulting from CAR-T cell infusion against B cell acute lymphoblastic leukemia (29). Whether tocilizumab can restore T cell counts in COVID-19 patients by suppressing IL-6 signaling remains uninvestigated.

The source of these cytokines during COVID-19 disease remains an open interesting issue. While previous studies have validated that the secretion of cytokines, including IL-6, IL-10, and TNF-α, mostly derives from T cells, macrophages and monocytes etc. (30, 31), based on our (inverse correlation) results, we suggest that the secretion of these cytokines does not originate from T cells. However, the cytokine storm in turn may promote apoptosis or necrosis of T cells, and consequently leads to their reduction. Our previous work demonstrated that monocytes and macrophages can produce pro-inflammatory cytokine during murine hepatitis virus strain-3 infection (32, 33), yet whether SARS-CoV-2 also triggers cytokine release from monocytes and macrophages in COVID-19 patients needs further investigation and current work around this is in progress in our hospital.

T cell exhaustion is a state of T cell dysfunction that arises during many chronic infections and cancer. It is defined by poor effector function, sustained expression of inhibitory receptors, and a transcriptional state distinct from that of functional effector or memory T cells (34). By FACS analysis, we found that both CD8+ T cells and CD4+ T cells have higher levels of PD-1 in virus infected patients, particularly in ICU patients (Figure 3). IL-10, an inhibitory cytokine, not only prevents T cell proliferation, but also can induce T cell exhaustion. Importantly, blocking IL-10 function has been shown to successfully prevent T cell exhaustion in animal models of chronic infection (35, 36). We demonstrate here that COVID-19 patients have very high levels of serum IL-10 following SARS-CoV-2 infection, while also displaying high levels of the PD-1 and Tim-3 exhaustion markers on their T cells, suggesting that IL-10 might be mechanistically responsible. The application of potent antiviral treatments to prevent the progression to T cell exhaustion in susceptible patients may thus be critical to their recovery. We have read with great interest the successful application of Remdesivir to cure a COVID-19 patient in the US, and clinical trials indicate that this drug may have significant potential as an antiviral (37, 38).

Taken together, we conclude that T cells are decreased and exhausted in patients with COVID-19. Cytokines such as IL-10, IL-6, and TNF-α might be involved in T cell reduction. Thus, new therapeutic measures are needed for treatment of COVID-19 ICU patients, and perhaps these are necessary even early on to preempt disease progression in higher-risk patients with low T cell counts.