Targeted therapies in retinoblastoma: GD2-directed immunotherapy following autologous stem cell transplantation and evaluation of alternative target B7-H3.

BACKGROUND: GD2-directed immunotherapy is highly effective in the treatment of high-risk neuroblastoma (NB), and might be an interesting target also in other high-risk tumors. METHODS: The German-Austrian Retinoblastoma Registry, Essen, was searched for patients, who were treated with anti-GD2 monoclonal antibody (mAb) dinutuximab beta (Db) in order to evaluate toxicity, response and outcome in these patients. Additionally, we evaluated anti-GD2 antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in retinoblastoma cell lines in vitro. Furthermore, in vitro cytotoxicity assays directed against B7-H3 (CD276), a new identified potential target in RB, were performed. RESULTS: We identified four patients with relapsed stage IV retinoblastoma, who were treated with Db following autologous stem cell transplantation (ASCT). Two out of two evaluable patients with detectable tumors responded to immunotherapy. One of these and another patient who received immunotherapy without residual disease relapsed 10 and 12 months after start of Db. The other patients remained in remission until last follow-up 26 and 45 months, respectively. In vitro, significant lysis of RB cell lines by ADCC and CDC with samples from patients and healthy donors and anti-GD2 and anti-CD276-mAbs were demonstrated. CONCLUSION: Anti-GD2-directed immunotherapy represents an additional therapeutic option in high-risk metastasized RB. Moreover, CD276 is another target of interest.

Automated production of specific T cells for treatment of refractory viral infections after allogeneic stem cell transplantation.

Therapy-resistant viral reactivations contribute significantly to mortality after hematopoietic stem cell transplantation. Adoptive cellular therapy with virus-specific T cells (VST) has shown efficacy in various single-center trials. However, the scalability of this therapy is hampered by laborious production methods. In this study we describe the in-house production of VST in a closed system (CliniMACS Prodigy® system, Miltenyi Biotec). In addition, we report the efficacy in 26 patients with viral disease following hematopoietic stem cell transplantation in a retrospective analysis (adenovirus, n=7; cytomegalovirus, n=8; Epstein-Barr virus, n=4; multi-viral, n=7). The production of VST was successful in 100% of cases. The safety profile of VST therapy was favorable (n=2 grade 3 and n=1 grade 4 adverse events; all three were reversible). A response was seen in 20 of 26 patients (77%). Responding patients had a significantly better overall survival than patients who did not respond (P<0.001). Virus-specific symptoms were reduced or resolved in 47% of patients. The overall survival of the whole cohort was 28% after 6 months. This study shows the feasibility of automated VST production and safety of application. The scalability of the CliniMACS Prodigy® device increases the accessibility of VST treatment.

Influence of ATLG serum levels on CD3/CD19-depleted hematopoietic grafts and on immune recovery in pediatric haplo-HSCT.

ABSTRACT: Anti-T lymphocyte globulin (ATLG) significantly reduces the risk of engraftment failure in allogeneic hematopoietic stem cell transplant (HSCT) but hampers posttransplant immune reconstitution. We hypothesized that in patients receiving haploidentical CD3/CD19-depleted grafts, these double-edged effects could be better balanced by attaining high ATLG serum concentrations before transplant but as low as possible on the day of transplant. Therefore, we moved the start of ATLG application to day -12 and determined serum concentrations of T-cell-specific ATLG in pediatric patients treated with 3 established dosing regimens (15, 30, or 60 mg/kg). Corresponding mean T-cell-specific ATLG serum concentrations at day 0 were 1.14, 2.99, or 12.10 µg/mL, respectively. Higher ATLG doses correlated with higher peak levels at days -8 and -7 and reduced graft rejection, whereas lower ATLG doses correlated with significantly faster posttransplant recovery of T and natural killer cells. The rate of graft-versus-host disease remained low, independent of ATLG doses. Moreover, in vitro assays showed that ATLG concentrations of 2.0 µg/mL and lower only slightly reduced the activity of natural killer cells, and therefore, the function of such effector cells might be preserved in the grafts. Pharmacokinetic analysis, compatible with linear first-order kinetics, revealed similar half-life values, independent of ATLG doses. Hence, the day on which a desired ATLG serum level is reached can be calculated before HSCT. Our retrospective study demonstrates the relevance of dosing and time of administration of ATLG on engraftment and immune recovery in ex vivo CD3/CD19-depleted haploidentical HSCT.

Ex vivo and in vivo T-cell depletion in allogeneic transplantation: towards less or non-cytotoxic conditioning regimens.

INTRODUCTION: Although tremendous progress has been made since the introduction of allogeneic hematopoietic stem cell transplantation (HSCT) decades ago, there are still many obstacles to overcome. A major obstacle is the presence of T-lymphocytes in the recipient and in the donor. Recipient-derived T-lymphocytes not eliminated by the conditioning regimen are a major barrier and can lead to mixed chimerism or to complete rejection of the graft. Donor-derived T-lymphocytes can induce severe acute and chronic Graft-versus-Host Disease (GvHD). AREAS COVERED: Currently published strategies for in vivo depletion of recipient-derived T-lymphocytes are discussed including the increase of the intensity of the conditioning regimen, the addition of anti-thymocyte globulin (ATG) or the anti-CD52 monoclonal antibody Campath. For the depletion or tolerization of the donor-derived T-lymphocytes, ex vivo-T-cell depletion methods, such as positive selection of CD34+ stem cells, negative depletion of CD3+ or TcRαß+ T-lymphocytes or the use of post-transplant cyclophosphamide (PTCy) have been developed. EXPERT COMMENTARY: All these currently used approaches have their disadvantages and new approaches should be investigated. In this review, we discuss current and propose new possible strategies to overcome the HLA barrier by using more specific T-cell directed therapies and/or by the combinations of current methods.

Recurrent SARS-CoV-2 Infection and Impaired Immunologic Response in a Pediatric Oncologic Patient While Treated With Radiochemotherapy.

Immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pediatric patients with malignant disease may be affected by tumor therapy. Here, we report the case of a child with rhabdomyosarcoma and recurrent SARS-CoV-2 infection. Immunologic responses, analyzed by T-cell activity and anti-viral IgG levels, were impaired and not durable as a result of intensive radiochemotherapy.