Immunotherapy with interleukin-2 and α-interferon after IL-2-activated hematopoietic stem cell transplantation for breast cancer

Abstract

Summary:We previously demonstrated findings suggestive of autologous GVHD in patients receiving IL-2-activated peripheral blood stem cells (PBSC) with IL-2 after transplantation. A pilot study was designed to test tolerability, feasibility and frequency of autologous GVHD and engraftment using IL-2 and ␣-IFN posttransplantation. After cyclophosphamide (6 g/m 2 ) and carboplatin (1800 mg/m 2 ), patients with high-risk stage II or III breast cancer received chemotherapy and rhG-CSF mobilized autologous PBSC that had been cultured in IL-2 for 24 h. Subcutaneous administration of IL-2 began on day 0 at 6 × 10 5 IU/m 2 /day for 5 of 7 days each week and continued for 4 weeks. Once engraftment occurred, ␣-IFN was initiated at a dose of 1 × 10 6 /m 2 /day subcutaneously for 30 days. Thirty-four consecutive patients with stage II (n = 20), IIIA (n = 6) and IIIB (n = 8) disease were treated. All patients were without evidence of disease at the time of transplantation. The average time required for the ANC to reach 500/mm 3 was 10 days (range: 8-11 days) and for platelets to reach 20 000/mm 3 was 10.7 days (range: 6-21 days). Forty-seven percent of patients (n = 16) completed the full course of immunotherapy; the remaining patients received attenuated doses due to patient's request (n = 6), development of temperature Ͼ38؇C (n = 3), development of neutropenia (n = 3), serious infection (n = 1) and miscellaneous reasons (n = 5). Four patients experienced transient moderate toxicities (level 3) including elevated liver function tests, nausea, rash and capillary leak syndrome. Pathological findings suggestive of skin GVHD developed in 43% of patients (12/28 patients) when skin biopsies were evaluated in a blinded fashion. At 13 months post-transplant (median; range: 5-24 months), 28 patients (82%) remain diseasefree. These results demonstrate the feasibility and toxicity of this regimen along with pathological findings compatible with autologous GVHD of the skin. Keywords: interleukin-2; ␣-interferon; breast cancer; stem cell transplantation; immunotherapy Hematopoietic stem cell (HSC) transplantation may improve disease-free survival for selected women with stage II-IV breast cancer. 1-3 Any attempt to further improve therapeutic efficacy by increasing chemotherapy dose may result in excessive nonhematologic toxicities. Immunomodulation, in conjunction with high-dose chemotherapy and HSC transplantation may offer a potential benefit by providing a non-cross-resistant mechanism of tumor cell kill with non-overlapping toxicities. In addition, immunotherapy following autologous HSC transplantation has been associated with the development of graft-versushost disease (GVHD). [4][5][6] The generation of autologous GVHD in patients undergoing autologous HSC transplantation using immunomodulation, has been described in patients with breast cancer, multiple myeloma, lymphoma and acute myelogenous leukemia. [7][8][9][10][11][12] In the allogeneic BMT setting, the existence of GVHD is presumed to be associated with a graft-versus-tumor...

IL-2-based immunotherapy after autologous transplantation for lymphoma and breast cancer induces immune activation and cytokine release: a phase I/II trial

“…Following initial reports of the feasibility and immunologic potential of post-transplant IL-2 immunotherapy, 5-7 many investigators explored IL-2 and/or IL-2-activated effectors for a variety of malignancies with encouraging but inconclusive results. [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] We previously reported the results of a phase I trial of post-autologous transplant s.c. IL-2 (Amgen Inc., Thousand Oaks, CA, USA). 4 In all, 12 patients (six lymphoma, six breast cancer) were enrolled on a dose-escalation study of s.c. IL-2 given for 84 days; the best-tolerated dose was 0.25 Â 10 6 U/m 2 /day.…”

Administration of low-dose interleukin-2 plus G-CSF/EPO early after autologous PBSC transplantation: effects on immune recovery and NK activity in a prospective study in women with breast and ovarian cancer

“…These observations are similar to those described by Laughlin et al, 26 who reported no relevant modifications of marrow regeneration using continous intravenous infusion of similar doses of IL-2 (40 000 Cetus units m 2 /day equivalent to 240 000 IU m 2 /day) early after BMT. Similarly, Meehan et al 27 observed no modification of engraftment time using higher IL-2 dosages (600 000 IU m 2 /day) subcutaneously. Our present study extends these findings to patients receiving concomitant IL-2/G-CSF/EPO.…”

In vitro generation of cytotoxic effectors activated by interleukin 2 (IL-2): comparison of autologous peripheral blood stem cells (PBSC) from adults and children

“…Two clinical studies in women with poor risk breast cancer demonstrated the cytotoxic activity of mobilised PBSC. [7][8][9] The prognosis of stage 4 neuroblastoma has improved significantly with high-dose chemotherapy combined or not with TBI and ASCT as consolidation therapy 1,2 but remains poor. The respective role of autograft contamination by tumour cells and of persistent minimal residual disease is not clear.…”

“…6 The early administration of low-dose IL-2 after transplantation of IL-2-activated PBSC was then demonstrated to be feasible in women with poor risk breast cancer. [7][8][9] In the light of these preliminary results we felt that children with solid tumours could benefit from HDC combined with immune modulation. The occurrence of spontaneous regressions, 10 intratumour lymphocyte infiltrates with T cell clonal expansion, 11 and the potential efficacy of immunotherapy 12 all argue in favour of a possible role of the immune system in the fight against neuroblastoma (NB), the most common paediatric tumour.…”