Intratumoral IL-12 delivery empowers CAR-T cell immunotherapy in a pre-clinical model of glioblastoma
Original author: Giulia Agliardi et al. Nat Commun (2021) (DOI: 10.1038/s41467-020-20599-x)
Summary
Content writer – Clinical
July 29, 2022
Introduction
Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer in adults. It accounts for about 60-70% of gliomas. The standard treatment regimen for GBM is tumor resection followed by radiotherapy and concomitant chemotherapy with temozolomide. However, GBM has high recurrence attributed to the infiltrative nature of the tumor, and also a dismal prognosis with a poor median survival of around 14 months, hence there is a need for more effective therapies. In this arena, immunotherapy treatment directed towards T-cells with tumor specificity may be a promising therapeutic strategy.
Research overview
The treatment with chimeric antigenic receptor (CAR) T-cells is preferable to treat intracranial tumors due to the ability of T- cells to access the central nervous system (CNS), and penetrate the infiltrative sites of the tumor, and show antitumor activity. But the CAR-T cells efficacy may be impaired by various adaptive immune-suppressive responses. CAR – T cell therapy alone was not sufficient to eradicate GBM. However, an additional or a combinational therapeutic option was added to overcome tumor heterogeneity and the altered tumor microenvironment (TME). In this scenario, Interleukin 12 (IL – 12), a proinflammatory cytokine with potent tumor suppressor activity has been implemented as a combination agent with CAR T- cells in the present study. IL – 12 directly supports the cytotoxic activity of T- cells as well as plays a role in reshaping the TME to achieve antitumor immunity.
Methodology
In the present study, in the first phase, an immunocompetent orthotopic syngeneic mouse model of GBM was used to evaluate the anti-tumor activity of EGFRvIII-specific murine CAR-T cells as a single agent which was administered by intravenous injection. Also, the efficacy of EGFRvIII-directed CAR-T cells in vivo in mice was tested. The first phase consisted of an evaluation of recombinant single-chain IL-12 fused to the Fc portion of murine IgG3 (hereafter called IL-12:Fc) as a single agent in an orthotopic syngeneic mouse model with GBM. In the second phase, a combinatorial immunotherapy approach was designed where the local intratumoral delivery of a single dose of IL-12:Fc was administered along with systemic (intravenous) CAR – T cell therapy. Tumor growth was monitored using a magnetic resonance imaging (1T-MRI) system by measuring the tumor volumes.
The results of the present study demonstrated that both the single therapies were only able to delay tumor growth to a certain extent, whereas the combination of systemic EGFRvIII-specific CAR infusion and local IL-12:Fc administration eliminated tumors in most treated mice and showed a synergistic effect on the overall survival. Moreover, combination treatment with IL-12:Fc and CAR-T cell therapy showed significantly improved survival as compared to either treatment alone. Also, local delivery of a single dose of IL-12 improves the efficacy of CAR-T cells. Therefore, the authors have reported that the data has demonstrated that combined IL-12 and CAR-T cell therapy promotes an effective and persistent anti-tumor response, even in the context of a poorly immunogenic model.
Impact of the research
The benefit of combined therapy of CAR - T cells and local IL – 12, is multifaceted as the administration of IL -12 at the tumor site improves the efficacy of CAR T – cells in aggressive and poorly immunogenic tumors and thus also affect the transferred CAR –T cells, T – cell compartment and the myeloid cells in TME in preclinical models which helps in reshaping the TME and achieving antitumor immunity. Hence, the present study showed that the local administration of IL – 12, overcomes the barriers which are encountered by the CAR-T cell therapy in GBM. Thus, the authors have suggested trials for clinical studies of the combinational approach of systemic CAR –T cell therapy along with intratumoral administration of IL-12 in patients with GBM.
