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Rapid immune recovery and graft-versus-host disease-like engraftment syndrome following adoptive transfer of Costimulated autologous T cells.

ABSTRACT: Previously, we showed that adoptive transfer of in vivo vaccine-primed and ex vivo (anti-CD3/anti-CD28) costimulated autologous T cells (ex-T) at day +12 after transplant increased CD4 and CD8 T-cell counts at day +42 and augmented vaccine-specific immune responses in patients with myeloma. Here, we investigated the safety and kinetics of T-cell recovery after infusing ex-T at day +2 after transplant.In this phase I/II two-arm clinical trial, 50 patients with myeloma received autografts after high-dose melphalan followed by infusions of ex-T at day +2 after transplant. Patients also received pretransplant and posttransplant immunizations using a pneumococcal conjugate vaccine only (arm B; n = 24) or the pneumococcal conjugate vaccine plus an HLA-A2-restricted microltipeptide vaccine for HLA-A2(+) patients (arm A; n = 26).The mean number of T cells infused was 4.26 x 10(10) (range, 1.59-5.0). At day 14 after transplant, the median CD3, CD4, and CD8 counts were 4,198, 1,545, and 2,858 cells/microL, respectively. Interleukin (IL)-6 and IL-15 levels increased early after transplant and IL-15 levels correlated significantly to day 14 T-cell counts. Robust vaccine-specific B- and T-cell responses were generated. T-cell infusions were well tolerated with no effect on hematopoietic recovery. Eight patients (16%) developed a T-cell "engraftment syndrome" characterized by diarrhea and fever that was clinically and histopathologically indistinguishable from grade 1 to 3 acute graft-versus-host disease (GVHD) of the gastrointestinal tract (seven patients) and/or grade 1 to 2 cutaneous GVHD (four patients).Adoptive T-cell transfers achieve robust T-cell recovery early after transplant and induce moderate-to-severe autologous GVHD in a subset of patients.

SUBMITTER: Rapoport AP

PROVIDER: S-EPMC2828291 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Rapid immune recovery and graft-versus-host disease-like engraftment syndrome following adoptive transfer of Costimulated autologous T cells.

Rapoport Aaron P AP Stadtmauer Edward A EA Aqui Nicole N Vogl Dan D Chew Anne A Fang Hong-Bin HB Janofsky Stephen S Yager Kelly K Veloso Elizabeth E Zheng Zhaohui Z Milliron Todd T Westphal Sandra S Cotte Julio J Huynh Hong H Cannon Andrea A Yanovich Saul S Akpek Gorgun G Tan Ming M Virts Kristen K Ruehle Kathleen K Harris Carolynn C Philip Sunita S Vonderheide Robert H RH Levine Bruce L BL June Carl H CH

Clinical cancer research : an official journal of the American Association for Cancer Research 20090609 13

<h4>Purpose</h4>Previously, we showed that adoptive transfer of in vivo vaccine-primed and ex vivo (anti-CD3/anti-CD28) costimulated autologous T cells (ex-T) at day +12 after transplant increased CD4 and CD8 T-cell counts at day +42 and augmented vaccine-specific immune responses in patients with myeloma. Here, we investigated the safety and kinetics of T-cell recovery after infusing ex-T at day +2 after transplant.<h4>Experimental design</h4>In this phase I/II two-arm clinical trial, 50 patien ...[more]

PMID: 19509133

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Project description:Myeloma-directed cellular immune responses after autologous stem cell transplantation (ASCT) may reduce relapse rates. We studied whether coinjecting the TLR-3 agonist and vaccine adjuvant Poly-ICLC with a MAGE-A3 peptide vaccine was safe and would elicit a high frequency of vaccine-directed immune responses when combined with vaccine-primed and costimulated autologous T cells.In a phase II clinical trial (NCT01245673), we evaluated the safety and activity of ex vivo expanded autologous T cells primed in vivo using a MAGE-A3 multipeptide vaccine (compound GL-0817) combined with Poly-ICLC (Hiltonol), granulocyte macrophage colony-stimulating factor (GM-CSF) ± montanide. Twenty-seven patients with active and/or high-risk myeloma received autografts followed by anti-CD3/anti-CD28-costimulated autologous T cells, accompanied by MAGE-A3 peptide immunizations before T-cell collection and five times after ASCT. Immune responses to the vaccine were evaluated by cytokine production (all patients), dextramer binding to CD8(+) T cells, and ELISA performed serially after transplant.T-cell infusions were well tolerated, whereas vaccine injection site reactions occurred in >90% of patients. Two of nine patients who received montanide developed sterile abscesses; however, this did not occur in the 18 patients who did not receive montanide. Dextramer staining demonstrated MAGE-A3-specific CD8 T cells in 7 of 8 evaluable HLA-A2(+) patients (88%), whereas vaccine-specific cytokine-producing T cells were generated in 19 of 25 patients (76%). Antibody responses developed in 7 of 9 patients (78%) who received montanide and only weakly in 2 of 18 patients (11%) who did not. The 2-year overall survival was 74% [95% confidence interval (CI), 54%-100%] and 2-year event-free survival was 56% (95% CI, 37%-85%).A high frequency of vaccine-specific T-cell responses were generated after transplant by combining costimulated autologous T cells with a Poly-ICLC/GM-CSF-primed MAGE-A3 vaccine.

Project description:BackgroundThe treatment of large osteochondral lesions of the talus (OLTs) is challenging due to the poor intrinsic reparative capability of the damaged articular cartilage. Autologous transfer of bone and periosteum has been used successfully in the treatment of large defects in animals, and therefore it was believed that this technique might show similar results in humans. The purpose of this study was to assess the outcome of an innovative technique for autologous transplantation of cancellous tibial graft with periosteal transfer in large OLTs.MethodsForty-one patients (22 females, 19 males), with a mean age of 34.9 years (range, 18-72 years), with a large OLT (>200 mm2) were treated with autologous bone graft and periosteum transfer. OLTs averaging 310 mm2 were identified on a preoperative computed tomography scan. The procedure consisted of malleolar osteotomy, curettage of sclerotic bone, autologous bone graft from the proximal tibia, and transfixion of periosteum over the graft. Outcome measures, including the pain visual analog scale (VAS), ankle range of motion (ROM), American Orthopaedic Foot & Ankle Society (AOFAS) score, and Foot & Ankle Disability Index (FADI), were compared between preoperative and 1 and 2 years following surgery.ResultsThere were significant improvements in VAS pain score from 7.7 before surgery to 1.1 at 1 year after surgery and 0.4 at 2 years or more after surgery. The AOFAS and FADI scores were also significantly improved from 40.3 and 53.3 preoperatively to 95 and 93.2 postoperatively at 1 year and 95 and 93.2 at 2 or more years postoperatively, respectively. Postoperative complications included 2 patients who required removal of medial malleolar osteotomy tension bands due to symptomatic hardware. There were no nonunions or malunions of the osteotomies and no donor site complications.ConclusionAutologous bone graft and periosteum transfer was an effective treatment for large OLTs leading to significant decreases in pain and improvement in functional scores at more than 2 years after surgery.Level of evidenceLevel IV, retrospective case series.

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Rapid immune recovery and graft-versus-host disease-like engraftment syndrome following adoptive transfer of Costimulated autologous T cells.

Publications

Rapid immune recovery and graft-versus-host disease-like engraftment syndrome following adoptive transfer of Costimulated autologous T cells.

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