Baseline Immune Status Predicts Response to Adoptive Therapy with CMV Cytotoxic T-Cells for Refractory CMV

Abstract

<h3>Background</h3> Adoptive cell therapy using CMV-specific cytotoxic T-cells (CMV CTLs) has demonstrated efficacy in treating CMV in the post HCT setting. However, little is known about the mechanism by which adoptively transferred CTLs exert durable responses. Therefore, we studied the relationship between response and recipient factors. <h3>Methods</h3> We retrospectively reviewed pediatric and adult patients (pts) who received primary or 3rd party donor CMV CTLs for the treatment of CMV viremia/disease after HCT between 9/2009 and 1/2018. Outcomes of interest were response to CMV CTLs and death from CMV. We evaluated these in relationship to time to start of CMV CTLs and IR using a CD4 count of 50 × 10⁶/L and of 200 × 10⁶/L as markers of IR. Pts whose CMV response was not attributable to CMV CTLs were excluded from analysis. <h3>Results</h3> Pts (n=102) were transplanted for malignant (n=83) and non-malignant (n=19) disease at a median age of 51.8 (range 0.3-73). Pts were treated with primary (n=25), 3rd party (n=74) and both (n=3) type of donor CMV CTLs. The median time from HCT to treatment was 127 days (range 29-2763). There was no difference in time to IR (p=0.4) or response to CMV CTLs between donor types (p=0.17). However, recipients with a baseline CD4>50 × 10⁶/L were significantly (p=0.015) more likely to respond to CMV CTLs (26/29, 90%) vs those with a baseline CD4<50 × 10⁶/L (30/49, 61%). There was no evidence of difference in time to achieve a CD4>50 × 10⁶/L in responding vs non-responding recipients. Using a conventional measure of IR as CD4>200 × 10⁶/L there was no evidence of difference in time to achieve IR between responders and non-responders. Responders (n=5) died less frequently from CMV than non-responders (n=12) (p=<0.0001). Responders (n=7) died from other infections as frequently as non-responders (n=3) (13 vs 17%, p=0.5). <h3>Conclusion</h3> We demonstrate that adoptive therapy with CMV CTLs may rely on recipient immune components to mediate durable response to therapy. Irrespective of the time from HCT, pts with a baseline CD4< 50 × 10⁶cells/L were less likely to respond to CMV CTLs. Response to CMV CTLs protected from CMV related death but not death from other infections.