Mesenchymal Stromal Cells Engineered To Express IL-12 for Breast Cancer Cellular Immunotherapy.
Notice bibliographique
Résumé
Abstract Interleukin 12 (IL-12), produced mostly by antigen presenting cells, is a heterodimeric Th1 cytokine which has been shown to induce a cellular immune response, cancer cell apoptosis, as well as anti-angiogenesis. Many studies have demonstrated the anti-cancer effectiveness of IL-12. However, significant toxicity from recombinant human IL-12 administration has been noted in phase I/II studies in advanced cancers. Therefore, sustained delivery of IL-12, avoiding toxic peaks seen with intermittent IV infusions, would be desirable. One means of delivering sustained and optimal amounts of IL-12 in cancer patients may be through a gene-enhanced cell therapy approach which our study assessed in a pre-clinical model of breast cancer. More specifically, we tested the use of an injectable subcutaneous implant comprising bone marrow-derived mesenchymal stromal cells (MSCs) gene-modified ex vivo to secrete IL-12 in mice with 4T1 breast cancer. Balb/c mice injected subcutaneously with the syngeneic 4T1 breast cancer cells at 2.5 x 104 cells/mouse received the following day, at the same location, Matrigel-embedded IL-12 gene-modified Balb/c-derived MSCs (IL-12 MSCs) or Matrigel-embedded control-vector modified MSCs (Control MSCs) at 106 cells/mouse. Tumor growth over time was determined in these two groups of mice, as well as in mice that received 4T1 cells only without any implants of MSCs (n=5-9/group). Our results revealed a substantial slowing of tumor progression in mice implanted with IL-12 MSCs as indicated by 100% of IL-12 mice being tumor-free on day 20 post-4T1 cell implantation, versus 0% of mice in both control groups, and with over 50% of IL-12 mice remaining tumor-free for over 50 days. Repeat experiments showed similar results. Analysis of plasma samples demonstrated significantly elevated levels of IL-12 and of interferon-γ in mice that received the implants of IL-12 MSCs, versus mice that received the Control MSCs. However, when tested in immunodeficient NOD-SCID mice, our approach revealed 0% tumor-free mice at day 20 post-implantation for all three groups, thus indicating that the anti-cancer effect seen in normal mice was mediated by bystander immune cells. In addition, we determined that the slowing of tumor growth was not due to systemic but to local delivery of IL-12, since IL-12 MSCs when injected in the flank contralateral to the 4T1 cells did not lead to any beneficial effect, all mice developing tumors similarly within 20 days. In an implant analysis experiment where 4T1 cells were admixed with MSCs in Matrigel and retrieved 2 weeks post-implantation, histopathology revealed substantially less tumor cells in implants with IL-12 MSCs as well as the presence of necrotic capillaries and necrotic tumor islets, in contrast to controls where most of the implant was occupied by tumor cells and with the presence of viable capillaries and tumor islets. Furthermore, we noted the beneficial effect of our gene-enhanced cell therapy strategy in the B16 mouse melanoma model as well. In conclusion, our investigation demonstrates the potential of employing autologous MSCs genetically engineered to secrete a therapeutic protein of interest, in this case IL-12, as part of a cell-based immunotherapy strategy for cancer therapy.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».