The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently intensifying across the world. The US alone accounts for nearly one-third of the global disease burden and approximately one-fifth of deaths. The number of reported cases has been doubling weekly in the US, emphasizing the contagiousness of the disease among the US population due to a lack of immunity to the novel virus.1
Epidemiological studies thus far indicate that disease fatality rates are higher in elderly patients with known comorbidities.2 Patients with immunocompromised states are at the highest risk of mortality from COVID-19. Patients with cancer, particularly those with hematological malignancies receiving active treatment, are severely immunocompromised.3 Among these, patients undergoing stem cell transplant or receiving immune-engaging therapy are the most vulnerable. While both the European Society for Blood and Marrow Transplantation and the American Society for Transplantation and Cellular Therapy have provided interim guidelines for the diagnosis and management of COVID-19 in the transplant setting, to our knowledge, no set of recommendations exists for patients who develop COVID-19 while receiving immunotherapy or increasingly popular advanced immune-engaging therapies.
Possible Risk Factors of Acute Respiratory Distress Syndrome and Mortality in COVID-19
COVID-19 carries a mortality rate of approximately 2% to 5%.2,4 This is considerably higher in comparison with the less than 1% mortality rate associated with influenza. While there is a critical need to better understand the mechanisms that lead to COVID-19’s progression to acute respiratory distress syndrome (ARDS), existing evidence suggests a SARS-CoV-2–induced immune dysfunction and hyperinflammatory state.2,5 The spike protein of SARS-CoV-2 binds to its target cells through angiotensin-converting enzyme 2 (ACE-2) receptors, expressed by the cells of several body organs, and hence leads to multiorgan failure.5 This leads to hyperactivation of inflammatory cells and macrophages, resulting in a hypercytokine state that may become fulminant and eventually lead to death.5 This hyperinflammatory state is practically indistinguishable from hemophagocytic lymphohistiocytosis, most commonly driven by viral infections in adults, or cytokine release syndrome (CRS), associated with chimeric antigen receptor (CAR) T-cell therapy.
Conventional Immunotherapy and COVID-19
While conventional cancer treatments (chemotherapy and radiation) directly damage both normal and cancerous cells, immune-engaging therapies harness patients’ own immune systems to specifically target tumor cells. Conventional immune checkpoint inhibitors (ICIs), such as programmed cell death 1 and cytotoxic T-lymphocyte antigen 4 inhibitors, restore the tumor immunosurveillance and revivify the immune system to target the tumor cells. Hence, ICI works by bolstering the immune system, which may result in autoimmunity.
With the preliminary immunological understanding of risk factors associated with ARDS and mortality in COVID-19, ICI-associated pneumonitis may further exacerbate pulmonary inflammation.6 Hence, patients receiving ICI who develop any respiratory symptom—new or worsening cough, runny nose, sore throat, congestion, new or worsening breathlessness, or suggestive radiological features—or who have contact with a patient with COVID-19 should be tested for COVID-19. For patients who reside in an area with a high prevalence of COVID-19 cases, either ICI should be postponed or a different cancer treatment plan should be pursued, as the clinical situation mandates. Patients diagnosed with COVID-19 who are not critically sick should have their ICI postponed until complete resolution of infection or wait for at least 2 weeks, whichever comes later. In the treatment of patients receiving ICI who develop critical illness due to COVID-19, immunosuppressive therapy should be considered in addition to immediate cessation of ICI. A retrospective multicenter study from China including 150 patients (with laboratory-confirmed infection of COVID-19) showed that C-reactive protein and interleukin-6 levels were considerably higher in the 68 patients (45.3%) who died in comparison with the 82 patients (54.6%) who were discharged healthy.5 Hence, the potential therapeutic armamentarium for COVID-19–associated ARDS could be similar to that used to treat CRS associated with CAR T-cells.7 These may include granulocyte-macrophage colony-stimulating factor inhibition, targeted cytokine blockade such as interleukin-1 (anakinra), interleukin 6 (tocilizumab, siltuximab, and sarilumab), and Janus kinase inhibition. Randomized clinical trials with exploratory arms are urgently needed; some of these are already underway.8,9
Emerging reports have suggested lymphopenia to be associated with intensive care unit admission and ARDS in patients with COVID-19.2,3 This finding, coupled with a lack of efficacy of steroid treatment for previous coronavirus-associated pandemics and evidence of prolonged viral shedding, suggests that steroids should best be avoided in treatment of COVID-19 until further evidence for their use emerges.10
Advanced Immune-Engaging Therapy and COVID-19
CAR T-cells are autologous T-cells that are engineered to target specific tumor antigens. These cells undergo in vivo expansion, and the resulting T-cell proliferation leads to an effective tumor kill. The immune activation, often hyperactivation, results in CRS.7 Hence any patient diagnosed with COVID-19, whether with mild flu-like symptoms or with ARDS, should not receive any form of CAR T-cells, neither for an approved indication nor in an experimental setting. Similar to circumstances in the ICI setting, once a patient is completely recovered from COVID-19 and remains well for at least 2 weeks after recovery, the patient may be considered eligible to undergo further CAR T-cell therapy. Extreme caution should be exercised, as discussed above, with bispecific T-cell engagers, (eg, blinatumomab), tumor-infiltrating lymphocytes, and other advanced immune-engaging therapies, such as adoptive T-cell transfer, interleukin-2, and cancer vaccines.
Given the mounting evidence of an exorbitant cytokine storm as the critical event that leads to multiorgan failure and death associated with COVID-19, immune-based treatments that are known to cause CRS will be best deferred. To this end, regional transplant societies’ recommendations and best judgment ought to be exercised to weigh the benefit of immune-engaging treatment—in an era when the kinetics of adaptive immune response to SARS-CoV-2 are not known—against the risk of underlying disease progression. If deemed necessary, the patient should undergo asymptomatic screening for COVID-19 prior to initiation, also keeping in view that the sensitivity of a polymerase chain reaction–based test is not known.
While longitudinal serological studies are awaited, emerging evidence suggests that primary SARS-CoV-2 may render natural immunity and could protect a survivor from subsequent infections. Although this is critical information for vaccine development, loss of lives with prior coronavirus outbreaks (severe acute respiratory syndrome–associated coronavirus and Middle East respiratory syndrome coronavirus) taught us that damage prevention is imperative and astronomically more effective than damage control, particularly for elderly patients and those with underlying conditions.
Corresponding Author: Muhammad Bilal Abid, MD, MRCP, Division of Hematology/Oncology, Department of Medicine, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226 (firstname.lastname@example.org).
Published Online: May 20, 2020. doi:10.1001/jamaoncol.2020.2367
Conflict of Interest Disclosures: None reported.
J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med
. 2020;46(5):846-848. doi:10.1007/s00134-020-05991-xPubMedGoogle Scholar
FS. Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced cancer: a systematic review and meta-analysis. JAMA Oncol
. 2016;2(12):1607-1616. doi:10.1001/jamaoncol.2016.2453PubMedGoogle ScholarCrossref
A multicenter, randomized controlled trial for the efficacy and safety of tocilizumab in the treatment of new coronavirus pneumonia (COVID-19). Chinese Clinical Trial Registry identifier: ChiCTR2000029765. Accessed May 11, 2020. http://www.chictr.org.cn/showprojen.aspx?proj=49409