Targeted immunotherapy for pediatric solid tumors

Kopp, Lisa M.; Katsanis, Emmanuel

doi:10.1080/2162402x.2015.1087637

Cited by 9 publications

(7 citation statements)

References 76 publications

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“…Because adult-onset NB probably develops over years, the acquisition of multistep somatic mutations might make these tumors more targetable by T-cells. Thus T-cell mediated immunotherapy including immune checkpoint inhibition, which has not hitherto been effective in pediatric solid tumors 48, 49 could potentially be more useful in adults, though clinical data on the use of such agents is currently unavailable.…”

Section: Discussionmentioning

confidence: 99%

Treatment and outcome of adult‐onset neuroblastoma

Suzuki

Kushner

Krämer

et al. 2018

Intl Journal of Cancer

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Adult-onset neuroblastoma is rare and little is known about its biology and clinical course. There is no established therapy for adult-onset neuroblastoma. Anti-GD2 immunotherapy is now standard therapy in children with high-risk neuroblastoma; however, its use has not been reported in adults. Forty-four adults (18-71 years old) diagnosed with neuroblastoma between 1979 and 2015 were treated at Memorial Sloan Kettering Cancer Center. Five, 1, 5 and 33 patients had INSS stage 1, 2, 3 and 4 diseases, respectively. Genetic abnormalities included somatic ATRX (58%) and ALK mutations (42%) but not MYCN-amplification. In the 11 patients with locoregional disease, 10-year progression-free (PFS) and overall survival (OS) was 35.4 ± 16.1% and 61.4 ± 15.3%, respectively. Among 33 adults with stage 4 neuroblastoma, 7 (21%) achieved complete response (CR) after induction chemotherapy and/or surgery. Seven patients with primary refractory neuroblastoma (all with osteomedullary but no soft tissue disease) received anti-GD2 antibodies, mouse or humanized 3F8. Antibody-related adverse events were similar to those in children, response rate being 71.4%. In patients with stage 4 disease at diagnosis, 5-year PFS was 9.7± 5.3% and most patients who were alive with disease at 5 years died of neuroblastoma over the next 5 years, 10-year OS being only 19.0 ± 8.2%. Patients who achieved CR after induction had superior PFS and OS (p = 0.006, p = 0.031, respectively). Adult-onset neuroblastoma appeared to have different biology from pediatric or adolescent NB, and poorer outcome. Complete disease control appeared to improve long-term survival. Anti-GD2 immunotherapy was well tolerated and might be beneficial.

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Section: Discussionmentioning

confidence: 99%

Treatment and outcome of adult‐onset neuroblastoma

Suzuki

Kushner

Krämer

et al. 2018

Intl Journal of Cancer

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“…However, CD33 is a normal myeloid surface antigen that likely requires gene editing to avoid myeloablative toxicity and severe CRS driven by on-target/off-tumor action of CD33 CAR-T cells ( 11 ). For osteosarcoma, suitable tumor targets are limited, but HER2, GD2/GD3, and NKG2D CAR-T cell treatments have been under investigation ( 5 , 6 , 12 ). For CAR-T cell therapies in general, solid tumors remain a significant therapeutic challenge due to the lack of ideal antigen targets, inter/intra-patient tumor heterogeneity, poor CAR-T cell infiltration/function, and the presence of an immunosuppressive microenvironment ( 13 , 14 ).…”

Section: Introductionmentioning

confidence: 99%

Preclinical Evaluation of Bispecific Adaptor Molecule Controlled Folate Receptor CAR-T Cell Therapy With Special Focus on Pediatric Malignancies

Chu

Wheeler

et al. 2019

Front. Oncol.

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Chimeric antigen receptor (CAR)-T cell therapy has transformed pediatric oncology by producing high remission rates and potent effects in CD19+ B-cell malignancies. This scenario is ideal as CD19 expression is homogeneous and human blood provides a favorable environment for CAR-T cells to thrive and destroy cancer cells (along with normal B cells). Yet, CAR-T cell therapies for solid tumors remain challenged by fewer tumor targets and poor CAR-T cell performances in a hostile tumor microenvironment. For acute myeloid leukemia and childhood solid tumors such as osteosarcoma, the primary treatment is systemic chemotherapy that often falls short of expectation especially for relapsed and refractory conditions. We aim to develop a CAR-T adaptor molecule (CAM)-based therapy that uses a bispecific small-molecule ligand EC17, fluorescein isothiocyanate (FITC) conjugated with folic acid, to redirect FITC-specific CAR-T cells against folate receptor (FR)-positive tumors. As previously confirmed in rodents as well as in human clinical studies, EC17 penetrates solid tumors within minutes and is retained due to high affinity for the FR, whereas unbound EC17 rapidly clears from the blood and from receptor-negative tissues. When combined with a rationally designed CAR construct, EC17 CAM was shown to trigger CAR-modified T cell activation and cytolytic activity with a low FR threshold against tumor targets. However, maximal cytolytic potential correlated with (i) functional FR levels (in a semi-log fashion), (ii) the amount of effector cells present, and (iii) tumors' natural sensitivity to T cell mediated killing. In tumor-bearing mice, administration of EC17 CAM was the key to drive CAR-T cell activation, proliferation, and persistence against FR+ pediatric hematologic and solid tumors. In our modeling systems, cytokine release syndrome (CRS) was induced under specific conditions, but the risk of severe CRS could be easily mitigated or prevented by applying intermittent dosing and/or dose-titration strategies for the EC17 CAM. Our approach offers the flexibility of antigen control, prevents T cell exhaustion, and provides additional safety mechanisms including rapid reversal of severe CRS with intravenous sodium fluorescein. In this paper, we summarize the translational aspects of our technology in support of clinical development.

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“…Therefore, significantly effective therapy in refractory pediatric solid tumors with the NCCV Cocktail‐1 vaccine alone could be challenging. In the future, novel immunotherapies, including those using immunomodulatory Abs and chimeric antigen receptor T cells, could show better clinical response and improved survival rates …”

Section: Discussionmentioning

confidence: 99%

Efficacy of the NCCV Cocktail‐1 vaccine for refractory pediatric solid tumors: A phase I clinical trial

et al. 2019

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Pediatric refractory solid tumors are aggressive malignant diseases, resulting in an extremely poor prognosis. KOC1, FOXM1, and KIF20A are cancer antigens that could be ideal targets for anticancer immunotherapy against pediatric refractory solid tumors with positive expression for these antigens. This nonrandomized, open‐label, phase I clinical trial evaluated the safety and efficacy of the NCCV Cocktail‐1 vaccine, which is a cocktail of cancer peptides derived from KOC1, FOXM1, and KIF20A, in patients with pediatric refractory solid tumors. Twelve patients with refractory pediatric solid tumors underwent NCCV Cocktail‐1 vaccination weekly by intradermal injections. The primary endpoint was the safety of the NCCV Cocktail‐1 vaccination, and the secondary endpoints were the immune response, as measured by interferon‐r enzyme‐linked immunospot assay, and the clinical outcomes including tumor response and progression‐free survival. The NCCV Cocktail‐1 vaccine was well tolerated. The clinical response of this trial showed that 4 patients had stable disease after 8 weeks and 2 patients maintained remission for >11 months. In 4, 8, and 5 patients, the NCCV Cocktail‐1 vaccine induced the sufficient number of peptide‐specific CTLs for KOC1, FOXM1, and KIF20A, respectively. Patients with high peptide‐specific CTL frequencies for KOC1, FOXM1, and KIF20A had better progression‐free survival than those with low frequencies. The findings of this clinical trial showed that the NCCV Cocktail‐1 vaccine could be a novel therapeutic strategy, with adequate effects against pediatric refractory solid tumors. Future large‐scale trials should evaluate the efficacy of the NCCV Cocktail‐1 vaccination.

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Targeted immunotherapy for pediatric solid tumors

Cited by 9 publications

References 76 publications

Treatment and outcome of adult‐onset neuroblastoma

Treatment and outcome of adult‐onset neuroblastoma

Preclinical Evaluation of Bispecific Adaptor Molecule Controlled Folate Receptor CAR-T Cell Therapy With Special Focus on Pediatric Malignancies

Efficacy of the NCCV Cocktail‐1 vaccine for refractory pediatric solid tumors: A phase I clinical trial

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