Outcomes following posttransplant virus-specific T-cell therapy in patients with sickle cell disease

Abstract

Hematopoietic stem cell transplantation (HSCT) is being increasingly used as a curative approach for sickle cell disease (SCD). With the risk of graft-versus-host disease (GVHD), especially in the human leukocyte antigen-mismatched donors, intense immunosuppression is required leading to an increased risk of viral infection. Post-HSCT, adoptive transfer of virus-specific T-cell (VST) therapies have not been well-studied in patients with SCD. Here, we report the outcomes of patients with SCD at a single-center who received VSTs after transplant to prevent or treat viral infections. Thirteen patients who received HSCT from human leukocyte antigen-matched (n = 9) or -mismatched (n = 4) donors for SCD were treated with a total of 15 VST products for the treatment or prophylaxis of multiple viruses (cytomegalovirus, Epstein-Barr virus, adenovirus, BK virus, human herpes virus 6 +/- human parainfluenza virus 3). Of the patients evaluated, 46.2% (n = 6)) received VSTs as treatment for viral infection. Eighty percent of patients with active viremia (n = 4/5) achieved remission of at least 1 target virus. Seven additional patients (53.8%) received VSTs prophylactically and 6 of 7 (85.7%) remained virus-free after infusion. No immediate infusion-related toxicities occurred, and severe de novo acute GVHD occurred in only 2 (15.4%) patients. Given the good safety profile, high-rate of clinical responses and sustained remissions when administered with standard antiviral treatments, the routine use of VSTs after HSCT as prophylaxis or treatment may improve the overall safety of transplant for patients with SCD.

Graphical abstract

Figure 1.

Anti-CMV T-cell activity and clinical response in patients treated with CMV-specific VSTs for active CMV infection. (A) Anti-CMV antigen (phosphoprotein 65 [PP65], immediate early protein-1 [IE1]) T-cell response of the CMV-specific VST products as detected by IFN-γ ELISpot assay. Anti-CMV antigen T-cell response and CMV viral load (IU or copies per milliliter) in the recipient PB post-VST infusion for patient P4, P5, P7 treated with CMV infection (B-D) and timing of concomitant standard antiviral treatment. PCR, polymerase chain reaction; SFU, spot forming units.

Figure 2.

Anti-EBV T-cell activity and clinical response in patients treated with EBV-specific VSTs for active EBV infection. (A) Anti-EBV antigen (EBNA1, LMP1, LMP2) T-cell response of the EBV-specific VST products as detected by IFN-γ ELISpot assay. Anti-EBV antigen T-cell response and EBV viral load (copies per milliliter) in the recipient PB post-VST infusion for patient P1 treated with EBV infection (B) and timing of concomitant standard antiviral treatment. EBNA, Epstein-Barr nuclear antigen; LMP, latent membrane protein; PCR, polymerase chain reaction; SFU, spot forming units.

Figure 3.

Anti-AdV T-cell activity and clinical response in patients treated with AdV-specific VSTs for active adenovirus (AdV) infection. (A) Anti-adenoviral antigen (hexon, penton) T-cell response of the AdV-specific VST products as detected by IFN-γ ELISpot assay. Anti-AdV antigen T-cell response and AdV viral load (copies per milliliter) in the recipient PB post-VST infusion for patient P3, P11 treated with AdV infection (B and C) and timing of concomitant standard antiviral treatment. PCR, polymerase chain reaction; SFU, spot forming units.

Figure 4.

Anti-BKV T-cell activity and clinical response in patients treated with BKV-specific VSTs for active BKV infection. (A) Anti-BKV antigen (viral capsid protein 1 [VP1], large T [LgT]) T-cell response of the BKV-specific VST products as detected by IFN-γ ELISpot assay. Anti-BKV antigen T-cell response and BKV viral load (copies per milliliter) in the recipient PB post-VST infusion for patient P4 treated with BKV infection (B) and timing of concomitant standard antiviral treatment. BKV, BK virus; PCR, polymerase chain reaction; SFU, spot forming units.

Figure 5.

Anti-HPIV3 and HHV6 T-cell activity and clinical response. (A) Anti-HPIV3 antigen (matrix, NP) T-cell response of the HPIV3-specific VST products as detected by IFN-γ ELISpot assay. Anti-HPIV3 antigen T-cell response in the recipient PB and detection of HPIV3 by PCR of a nasal swab post-VST infusion for prophylaxis against HPIV3 (B-E). (F) Anti-HHV6 antigen (U54, V90) T-cell response of the HHV6-specific VST products as detected by IFN-γ ELISpot assay. (G-J) Anti-HHV6 antigen T-cell response and HHV6 viral load (copies per milliliter) in the recipient PB post-VST infusion for prophylaxis against HHV6. HHV6, human herpes virus 6; HPIV3, human parainfluenza virus 3; NP, nucleocapsid: PCR, polymerase chain reaction; SFU, spot forming units.

Figure 6.

Time to detection of response to target viral antigens. (A) Time to detection of T-cell response to CMV for patients receiving VSTs as treatment (green; n = 4) and patients treated prophylactically (blue; n = 8). Time to detectable responses differed between those treated for infection vs prophylaxis (P = .019). Time to detection of T-cell response to EBV (B) for patients receiving VSTs as treatment (green; n = 2) and patients treated prophylactically (blue; n = 11). Time to detectable responses differed between those treated for infection vs prophylaxis (P = .002). Time to detection of T-cell response to Adv (C) for patients receiving VSTs as treatment (green; n = 2) and patients treated prophylactically (blue; n = 11). No difference in time to detectable response between treatment and prophylactic groups (P = .76). Time to detection of T-cell response to BKV (D) for patients receiving VSTs as treatment (green; n = 2) and patients treated prophylactically (blue; n = 3). No difference in time to detectable response between treatment and prophylactic groups (P = .617). Time to detection of T-cell response to HHV6 (E) and HPIV3 (F) for patients treated prophylactically (n = 4). Adv, adenovirus; BKV, BK virus; CMV, cytomegalovirus; HHV6, human herpes virus 6; HPIV3, human parainfluenza virus 3.