Effect of administering subsequent immune checkpoint inhibition in cancer patients with prior COVID-19 infection

Dear Editor,

We read with interest the recent article published by Skevaki C et al who described the laboratory characteristics of patients infected with the novel SARS-CoV-2 virus,¹ which indicated that patients with COVID-19 have varying degrees of multiple organ dysfunction. Coronavirus disease 2019 (COVID-19) is characterized by symptomatology from immune hyperactivation against normal tissues such as the lungs. Because immune checkpoint inhibitors (ICIs) are intended to galvanize the immune system, it is imperative to evaluate the effect of ICI therapy in patients who have recovered from prior COVID-19.

In this study, we collected and analyzed data from 8 cancer patients with SARS-CoV-2 infection history (negative for viral RNA and positive for serum antibodies) who received subsequent immunotherapy from four hospitals, including Hubei Cancer Hospital, Union Hospital, People's Hospital of Dongxihu District and The Fifth Hospital of Wuhan. All patients had been diagnosed with COVID-19 via positive for nucleic acid testing before. We reviewed the medical records, including SARS-CoV-2 nucleic acid and antibody testing, chest computed tomography (CT), biochemical markers, and routine bloodwork and treatment data of all cancer patients with prior COVID-19 infection from March 9 to July 29, 2020. Confirmation of prior COVID-19 infection was defined as positive SARS-CoV-2 antibody testing by the colloidal gold immunoassay (Innovita, Tangshan, Hebei, China) and negative for viral nucleic acid by real-time reverse transcriptase PCR (rRT-PCR). The median age was 58 years (range: 41–72), and 63% patients were men. Four (50%) patients had a history of smoking and three (38%) patients had chronic diseases. All cases harbored positive serum antibodies: 1 was negative for immunoglobulin G (IgG⁻) and positive for immunoglobulin M (IgM⁺), 6 were IgG⁺ IgM⁻ and 1 was IgG⁺ IgM⁺. Nasopharyngeal cancer was the most frequent neoplasm (3/8 [38%] patients), followed by lung cancer (2/8 [25%] patients) (Table 1 ). Two (25%) patients had received ICI therapy prior to initially developing COVID-19, and 6 (75%) patients were ICI therapy-naïve.

Table 1.

Clinical characteristics of cancer patients receiving systemic therapy with prior SARS-CoV-2 infection.

Patient No.	Sex	Age	PS	Cancer diagnosis	Staging	Chronic diseases	Systemic therapy	Time of nucleic acid testing
1	Female	59	1	NPC	rT0N1M0	None	2 cycles of GP and 2 cycles of GP +PD-1 inhibitor	April 21; May 15; June 3; June 6; June 30; July 20
2	Male	41	1	NPC	T3N2M0	None	2 cycles of GP + PD-1 inhibitor; radiotherapy + 2 cycles of DDP + PD-1 inhibitor	March 25; April 17; May 29
3	Female	48	1	NPC	T3N1M0	None	Radiotherapy + 2 cycles of PD-1 inhibitor; 1 cycle of TP	April 26, May 8; June 10; June 15
4	Male	72	1	NSCLC	T3N1M0	Hypertension; Cardiovascular disease; COPD	2 cycles of abraxane and 2 cycles of abraxane + nedaplatin + PD-1 inhibitor	March 23; April 1; April 3; May 5; June 3; June 29
5	Male	64	1	NSCLC	T2N2M0	Cardiovascular disease	2 cycles of PD-1 inhibitor	April 18; May 12; May 26; June 9; July 17
6	Male	71	1	Soft tissue sarcoma	T3N0M0 G3	None	2 cycles of gemcitabine + anlotinib + PD-1 inhibitor	May 20; June 3; June 4; June 29
7	Female	51	1	Rectal cancer	rT0N0M1	None	4 cycles of XELOX + PD-1 inhibitor	April 16; May 5; May 29; July 1
8	Male	57	1	Esophagus cancer	T4aN2M0	Hypertension; Diabetes	3 cycles of capecitabine + nedaplatin + PD-1 inhibitor	March 20; June 1; July 2

Abbreviations: NPC, nasopharyngeal cancer; NSCLC, non-small cell lung cancer; COPD, chronic obstructive pulmonary disease; GP, gemcitabine and cisplatin; PD-1, programmed cell death protein 1; XELOX, oxaliplatin + capecitabine.

Three (38%) patients received a combination of anti-PD-1 agents with chemotherapy. Two (25%) patients were treated with immunotherapy alone. Two (25%) patients received combinatorial anti-PD-1 ICI with radiotherapy ± chemotherapy. One (13%) patient received anti-PD-1 with anlotinib.

The median follow-up from initial administration of ICI therapy was 83 days (IQR: 64–98). At the time of last follow-up, all patients remained negative for SARS-CoV-2 RNA nucleic acid, without suspicious changes on chest CT. Five (63%) patients experienced altered immunoglobulin test results. Specifically, 3 (38%) patients who were initially IgG⁺ IgM⁻became IgG⁻IgM⁻ after 25, 42, and 62 days of ICI therapy. Another was initially IgG⁺ IgM⁺ but became IgG⁺ IgM⁻after 23 days, and the final patient (initially IgG⁻ IgM⁺) became IgG⁻ IgM⁻ following 28 days of ICI therapy.

Systemic therapies were tolerated well in this cohort. Three patients developed grade 2 myelosuppression and one patient had hypothyroidism. Only one patient had grade 3 myelosuppression.

Cancer patients are a vulnerable population to COVID-19, and delaying therapies such as ICIs risks disease progression. It have reported that SARS-CoV-2 can reemerge in recovered (with negative viral RNA) patients,² and some studies have reported hepatitis B virus (HBV) or tuberculosis reactivation in cancer patients undergoing ICI therapy.^{3 , 4} Thus, it became essential to evaluate the safety of ICIs in patients recovered from prior COVID-19 infection. Importantly, this study did not observe a single case of disease reactivation or immune hyperactivation from ICI therapy.

Patients with COVID-19 have varying degrees of multiple organ dysfunction.^{5 , 6} The rates of liver dysfunction, acute kidney injury, and cardiac injury can be as high as 29%, 29% and 23%, respectively, in critically ill patients.⁶ From our analysis, our data demonstrate that cancer patients with prior COVID-19 infection who undergo ICI therapy do not show an overtly increased susceptibility to organ dysfunction in the short term. Although the quality of evidence is overall low, our study may help add important data to this emerging issue.

Our study has several limitations, in addition to its retrospective nature. According to the COVID-19 Diagnostic Criteria,⁷ viral serum antibodies are indeed valid for diagnosis; however, false positives/negatives can still occur. Additionally, the number of such cases herein remains relatively small, and a larger sample size in patients with cancer is needed to validate these findings, including a deeper understanding regarding the diverse types of ICIs as well as the impact of combinatorial therapies.

Declaration of Competing Interest

All other authors declare no competing interests.