TABLE 1.
Cytomegalovirus (CMV)‐specific Adoptive T cell therapy (ACT) clinical studies
| Method of T cell manufacturing | Purpose | Infused cells | Source of T cell | Antiviral response |
|---|---|---|---|---|
|
Direct isolation of Virus‐specific T cell 1. Short‐time ex vivo stimulation and Cytokine capture system (INF‐γ‐capture) | ||||
| Peggs et al (2010) (phase I–II) | Prophylactic a or Preemptive a | CMV‐specific CD4+ and CD8+ T cells | CMV seropositivedonors |
• In prophylactic treatment, none of the patients required antiviral drugs within the next 6 months. • In preemptive treatment, 9 out of 11 patients required antiviral drugs. • CMV‐reactive CD4+ cells were detected in five out of six patients within 2 weeks of infusion. • CD8+ T cells were detected in seven patients within 2 weeks. • The patients who received the lowest dose of CMV‐specific T cells showed the slowest both CD4+ (3 weeks) and CD8+ (8 weeks) T cell immunity reconstitution. |
| Feuchtinger et al (2010) | Therapeutic for refractory CMV infection and CMV disease | CMV‐specific CD4+ and CD8+ T cells | CMV seropositive donors |
• In 15 out of 18 cases (85%) CMV viremia cleared or the viral load (1 log) reduced significantly. • Only three patients did not response to adoptive pp65‐specific T cells transfer. • All cases showed in vivo expansion of CD4+ as well as CD8+ T cell. |
| Meij et al (2012) (phase I‐II) |
Therapeutic for refractory CMV |
CMV‐specific CD8+ T cells |
CMV seropositive donors or autologous |
• In all patients, CMV DNA load turned negative and CMV‐specific T cells detected in the PB. • CMV‐specific T cells in PB were CD8+ effector and memory T cells. |
| Mackinnon et al (2007) | Preemptive and prophylactic | CMV‐specific CD4+ and CD8+ T cells | CMVseropositive donors |
• In 8 out of 23 patients who received cultured CMV‐specific T cells viral DNA cleared without antiviral drugs. • All patients (n = 7) showed in vivo expansion of CMV‐reactive T cells. • Viral titers decreased within 5 days. CMV‐reactive T cells represented a mean of 9.0% CD4+ cells and 7.3% CD8+ cells in 2–4 weeks. |
| Ingels et al (2020) (case report) | Therapeutic for multidrug resistant CMV infection | CMV‐specific CD4+ and CD8+ T cells | CMV seropositive donors |
• CMV‐specific CD4+ T cells in the PB, expanded, and reached a frequency similar to the donor in 2 weeks after infusion and remained stable during the follow‐up period of 8 weeks. • CMVpp65‐specific CD8+ T even exceeded the frequencies found in healthy CMV seropositive individuals. • Reduction of CMV DNA copies in PB to <500 IU/mL |
|
Direct isolation of virus‐specific T cell 2. Peptide‐MHC (pMHC) multimer | ||||
| Cobbold et al (2005) | Preemptive and therapeutic | CMV‐ specific CD8+ T cells | CMV seropositivedonors |
• CTL response detected between 12 and 30 days after adoptive transfer • CMV viremia reduced in all cases and the infection cleared in 90% of patients. • CMV viral load reduced in one patient with refractory CMV infection |
| Schmitt et al (2010) | Therapeutic | CMV‐specific CD8+ T cells | CMV‐seropositivedonors |
• CMV‐specific CD8+ T cells had an effector memory phenotype • The clearance of the CMV antigenemia was persistent. • Treatment with toxic antiviral drugs discontinued. |
| Neuenhahn et al (2017) (Phase I‐IIa) |
Therapeutic for drug‐refractory CMV infection |
CMV‐specific CD8+ T cells |
CMV‐seropositivedonors or CMV‐seropositive Third‐party donors |
In treated D+ patients: • CMV‐specific T cells detected in 2 to 3 weeks after transfer. • Treatment resulted in 62.5% complete and 25% partial responses. In treated D− patients who received TPD‐derived CMV‐ specific T cells • CMV‐specific T cells were not detectable in 62.5% of patients. • Complete virus load response observed in 37.5% of patients. • T cell expansion triggered by a secondary viremic episode after adoptive transfer. • High HLA concordance between patient and TPD is an important requirement for successful virus‐specific ACT. |
| Ex vivo expansion of virus‐ specific T cells | ||||
| Riddell et al (1992) | Prophylactic | CMV‐specific CD8+ T cells |
CMV‐seropositive donors |
• CMV‐specific CD8+ T cell detected 48 hours after the first T cell infusion. • Immune responses increased after each cell infusion. • After the third cell infusion, lytic activity magnified in all recipients. |
| Walter et al (1995) | Prophylactic | CMV‐specific CD8+ T cells | CMV‐seropositivedonors |
• Cytotoxic T cells specific for CMV reconstituted in all patients. • Transferred clones persisted for at least 12 weeks. • Cytotoxic‐T‐cells activity declined in patients deficient in CD4+ T‐helper cells specific for CMV. • CMV viremia and disease did not develop in any of the 14 patients. |
| Einsele et al (2002) |
Therapeutic for drug‐refractory CMV infection |
CMV‐specific CD4+ and CD8+ T cells | CMV‐seropositivedonors |
• CMV viral load dropped despite antiviral drugs cessation in all patients. • Complete response detected in around 72% of patients. • Transient reductions in viral load detected in two out of seven patients who received an intensified immune suppression at the time of or after T‐cell therapy. |
| Peggs et al (2004) | Preemptive and therapeutic | CMV‐specific CD4+ and CD8+ T cells | CMV seropositive donor |
• In eight patients (50%) viral DNA cleared without antiviral drugs. • CD8+ T cell numbers increased within 4 weeks in all cases. • A low incidence of late CMV reactivation was observed. |
| Micklethwaite et al (2007) | Prophylactic | CMV‐specific CD8+ T cells | CMV seropositive donor |
• Specific T cells raised within the first 7 days after transferring in six out of nine recipients. • CMV reactivated in two recipients without pharmacotherapy or CMV disease development. • Specific T cells detected for the following 3 months. |
| Micklethwaite et al (2008) | Prophylactic | CMV‐specific CD4+ and CD8+ T cells | CMV seropositive donor |
• All 12 patients demonstrated CMV‐specific immunity for at least one time point after ACT. • Low‐level DNAemia was detected in four patients after infusion. |
|
Peggs et al (2009) (open‐label phase II) |
Prophylactic, preemptive, and therapeutic |
CMV‐specific CD4+ and CD8+ T cells | CMV seropositive donor |
• In ACT prophylactic therapy, 30% of patients showed a primary CMV infection required antiviral therapy. • All 10 patients treated pre‐emptively required antiviral drugs due to the high viral titers. • CD8+ T cells number increased to the normal reference interval within 4 weeks in 28 patients. • CD4+ T cells count increased less rapidly. • The median pp65‐specific T cells number decreased by 3 months following transfer but were maintained at protective levels against uncontrolled viral replication. |
| Bao et al (2012) | Therapeutic for persistent or drug‐refractory CMV infection | CMV specific CD8+ T cell | CMV seropositive donor |
• In five out of the seven new onset patients, CMV‐specific CTL activity detected within 4 to 6 weeks post infusion. • Among all seven patients with persistent CMV who received CMV‐specific CTL infusions, four patients developed specific cytotoxicity 4 weeks, and one patient developed specific cytotoxicity 6 weeks post‐infusion. |
| Blyth et al (2013) (phase II) | Prophylactic | CMV‐specific CD8+ T cells | CMV‐seropositive donors |
• The incidence of CMV reactivation in the 50 patients treated with CTL was 26/50 (52%). In 9 out of 26 patients with CMV reactivation, antiviral medications were required. |
Prophylactic therapy is an approach to prevent CMV infection posttransplant. Preemptive therapy is preventive approach for CMV infection following viremia detection and before the onset of symptoms or tissue invasion.