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. 2021 Jan 26;5(2):496-503.
doi: 10.1182/bloodadvances.2020002735.

Adoptive therapy with CMV-specific cytotoxic T lymphocytes depends on baseline CD4+ immunity to mediate durable responses

Vanessa A Fabrizio  1   2 , M Irene Rodriguez-Sanchez  1 , Audrey Mauguen  3 , Parastoo B Dahi  4 , Ekaterina Doubrovina  1   4 , Richard J O'Reilly  1 , Susan E Prockop  1   2
Affiliations

Adoptive therapy with CMV-specific cytotoxic T lymphocytes depends on baseline CD4+ immunity to mediate durable responses

Vanessa A Fabrizio et al. Blood Adv. .

Abstract

Adoptive cell therapy using cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CMV-CTLs) has demonstrated efficacy posttransplant. Despite the predicted limited engraftment of CMV-CTLs derived from third-party donors, partially matched third-party donor-derived CMV-CTLs have demonstrated similar response rates to those derived from primary hematopoietic cell transplantation donors. Little is known about the mechanisms through which adoptive cellular therapies mediate durable responses. We performed a retrospective analysis of patients receiving CMV-CTLs for treatment of CMV viremia and/or disease after allogeneic transplant between September of 2009 and January of 2018. We evaluated whether response to adoptively transferred CMV-CTLs correlated with immune reconstitution (IR), using validated CD4+ IR milestones of 50 × 106/L and 200 × 106/L. In this analysis, a cohort of 104 patients received CMV-CTLs derived from a primary transplant donor (n = 25), a third-party donor (n = 76), or both (n = 3). Response to therapy did not increase the likelihood of achieving CD4+ IR milestones at 1 (P = .53 and P > .99) or 2 months (P = .12 and P = .33). The origin of CMV-CTLs did not impact subsequent CD4+ IR. CMV-CTLs appeared to interact with host immunity in mediating responses. Recipients with a baseline CD4 >50 × 106/L had higher response to therapy (P = .02), improved overall survival (P < .001), and protection from CMV-related death (P = .002). Baseline endogenous immunity appears to improve CMV-related and overall survival in this cohort and can be an important marker at the initiation of therapy.

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Conflict of interest statement

Conflict-of-interest disclosure: R.J.O. and E.D. have received consulting fees and grant support from Atara Biotherapeutics, the Starr Cancer Consortium, and National Cancer Institute P01 CA23766. When Atara Biotherapeutics licensed banks of Epstein-Barr virus and CMV T cells, R.J.O. and E.D. received part of the royalties paid to MSKCC. MSKCC holds several patents related to this work on which R.J.O. and E.D. are inventors. S.E.P. receives support for the conduct of sponsored trials from Atara Biotherapeutics, Mesoblast, and Jasper. S.E.P. is an inventor of intellectual property licensed to Atara Biotherapeutics by MSKCC; S.E.P. assigned all rights to MSKCC and has no financial interest in Atara Biotherapeutics. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Response did not affect the achievement of either IR milestone at select time points. (A) Percentage of patients who achieved IR (CD4 ≥50 × 106/L) at different time points according to response (1-month P = .53; 2-month P = .12; 3-month P = .08). (B) Percentage of patients who achieved IR (CD4 ≥200 × 106/L) at different time points according to response (1-month P > .99; 2-month P = .33; 3-month P = .26).
Figure 2.
Figure 2.
Response to CMV-CTLs differs according to baseline CD4+counts. Cumulative rate of response to CMV-CTLs between baseline CD4 ≥50 × 106/L and baseline CD4 <50 × 106/L (P = .02).
Figure 3.
Figure 3.
The log of CD4+and CD8+over time does not differ between donor types. (A) Mean and 95% CI for log of CD4+ over time by donor type. The dashed line represents the CD4 = 200 × 106/L threshold (P = .28). (B) Mean and 95% CI for log of CD8+ over time by donor type (P = .13).
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