Ultra low-dose IL-2 for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation mediates expansion of regulatory t cells without diminishing antiviral and antileukemic activity

Alana A. Kennedy-Nasser, Stephanie Ku, Paul Castillo-Caro, Yasmin Hazrat, Meng Fen Wu, Hao Liu, Jos Melenhorst, A. John Barrett, Sawa Ito, Aaron Foster, Barbara Savoldo, Eric Yvon, George Carrum, Carlos A. Ramos, Robert A. Krance, Kathryn Leung, Helen E. Heslop, Malcolm K. Brenner, Catherine M. Bollard

Research output: Contribution to journalArticle

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Abstract

Purpose: GVHD after allogeneic hematopoietic stem cell transplantation (alloSCT) has been associated with low numbers of circulating CD4+CD25+FoxP3+ regulatory T cells (Tregs). Because Tregs express high levels of the interleukin (IL)-2 receptor, they may selectively expand in vivo in response to doses of IL-2 insufficient to stimulate T effector T-cell populations, thereby preventing GVHD. Experimental Design: We prospectively evaluated the effects of ultra low-dose (ULD) IL-2 injections on Treg recovery in pediatric patients after alloSCT and compared this recovery with Treg reconstitution post alloSCT in patients without IL-2. Sixteen recipients of related (n = 12) or unrelated (n = 4) donor grafts received ULD IL-2 post hematopoietic stem cell transplantation (HSCT; 100,000-200,000 IU/m2 3 per week), starting <day 30 and continuing for 6 to 12 weeks. Results: No grade 3/4 toxicities were associated with ULD IL-2. CD4+CD25+FoxP3+ Tregs increased from a mean of 4.8% (range, 0%-11.0%) pre IL-2 to 11.1% (range, 1.2%-31.1%) following therapy, with the greatest change occurring in the recipients of matched related donor (MRD) transplants.NoIL-2 patients developed grade 2-4 acute GVHD (aGVHD), compared with 4 of 33 (12%) of the comparator group who did not receive IL-2. IL-2 recipients retained T cells reactive to viral and leukemia antigens, and in the MRD recipients, only 2 of 13 (15%) of the IL-2 patients developed viral infections versus 63% of the comparator group (P = 0.022). Conclusions: Hence,ULDIL-2 is well tolerated, expands a Treg population in vivo, and may be associated with a lower incidence of viral infections and GVHD.

Original languageEnglish (US)
Pages (from-to)2215-2225
Number of pages11
JournalClinical Cancer Research
Volume20
Issue number8
DOIs
StatePublished - Apr 15 2014
Externally publishedYes

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Hematopoietic Stem Cell Transplantation
Interleukin-2
Antiviral Agents
Tissue Donors
Virus Diseases
T-Lymphocytes
Viral Antigens
Interleukin-2 Receptors
Regulatory T-Lymphocytes
Population
Leukemia
Research Design
Pediatrics
Transplants
Injections
Incidence

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Ultra low-dose IL-2 for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation mediates expansion of regulatory t cells without diminishing antiviral and antileukemic activity. / Kennedy-Nasser, Alana A.; Ku, Stephanie; Castillo-Caro, Paul; Hazrat, Yasmin; Wu, Meng Fen; Liu, Hao; Melenhorst, Jos; Barrett, A. John; Ito, Sawa; Foster, Aaron; Savoldo, Barbara; Yvon, Eric; Carrum, George; Ramos, Carlos A.; Krance, Robert A.; Leung, Kathryn; Heslop, Helen E.; Brenner, Malcolm K.; Bollard, Catherine M.

In: Clinical Cancer Research, Vol. 20, No. 8, 15.04.2014, p. 2215-2225.

Research output: Contribution to journalArticle

Kennedy-Nasser, AA, Ku, S, Castillo-Caro, P, Hazrat, Y, Wu, MF, Liu, H, Melenhorst, J, Barrett, AJ, Ito, S, Foster, A, Savoldo, B, Yvon, E, Carrum, G, Ramos, CA, Krance, RA, Leung, K, Heslop, HE, Brenner, MK & Bollard, CM 2014, 'Ultra low-dose IL-2 for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation mediates expansion of regulatory t cells without diminishing antiviral and antileukemic activity', Clinical Cancer Research, vol. 20, no. 8, pp. 2215-2225. https://doi.org/10.1158/1078-0432.CCR-13-3205
Kennedy-Nasser, Alana A. ; Ku, Stephanie ; Castillo-Caro, Paul ; Hazrat, Yasmin ; Wu, Meng Fen ; Liu, Hao ; Melenhorst, Jos ; Barrett, A. John ; Ito, Sawa ; Foster, Aaron ; Savoldo, Barbara ; Yvon, Eric ; Carrum, George ; Ramos, Carlos A. ; Krance, Robert A. ; Leung, Kathryn ; Heslop, Helen E. ; Brenner, Malcolm K. ; Bollard, Catherine M. / Ultra low-dose IL-2 for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation mediates expansion of regulatory t cells without diminishing antiviral and antileukemic activity. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 8. pp. 2215-2225.
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AU - Ramos, Carlos A.

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