Interferon gene therapy reprograms the leukemia microenvironment inducing protective immunity to multiple tumor antigens

Abstract

Immunotherapy is emerging as a new pillar of cancer treatment with potential to cure. However, many patients still fail to respond to these therapies. Among the underlying factors, an immunosuppressive tumor microenvironment (TME) plays a major role. Here we show that monocyte-mediated gene delivery of IFNα inhibits leukemia in a mouse model. IFN gene therapy counteracts leukemia-induced expansion of immunosuppressive myeloid cells and imposes an immunostimulatory program to the TME, as shown by bulk and single-cell transcriptome analyses. This reprogramming promotes T-cell priming and effector function against multiple surrogate tumor-specific antigens, inhibiting leukemia growth in our experimental model. Durable responses are observed in a fraction of mice and are further increased combining gene therapy with checkpoint blockers. Furthermore, IFN gene therapy strongly enhances anti-tumor activity of adoptively transferred T cells engineered with tumor-specific TCR or CAR, overcoming suppressive signals in the leukemia TME. These findings warrant further investigations on the potential development of our gene therapy strategy towards clinical testing.

Mechanisms of Leukemia Immune Evasion and Their Role in Relapse After Haploidentical Hematopoietic Cell Transplantation

“…A phase I trial testing the IL-15 super-agonist complex ALT-803 in patients relapsing after allo-HCT showed a very promising response rate (19% of evaluable patients), correlated to the expansion of both NK and T cells (187). Recently, novel approaches to transfer high concentration of cytokines to the tumor site and reduce their systemic effects are emerging, including gene therapy "Trojan Horse" strategies (188) and the use of lipid nanoparticles to convey to the tumor site mRNAs encoding cytokines (189).…”

Lentiviral Vector Production Titer Is Not Limited in HEK293T by Induced Intracellular Innate Immunity

“…However, it is likely that novel gene therapies will deploy constructs that directly activate innate immune and inflammatory responses. For example, gene delivery of type 1 IFN itself has been proposed in anti-tumor strategies 33,34 and modified T cell receptors such as CARs are likely to activate signaling pathways. We therefore set out to measure the effect of an artificial and potent innate immune response on LV production in HEK293T cells.…”

Genetic engineering of hematopoiesis: current stage of clinical translation and future perspectives

“…The demyelinating leukodystrophies Adrenoleukodystrophy (ALD) and Metachromatic Leukodystrophy (MLD), and the combined immune and platelet deficiency Wiskott-Aldrich syndrome (WAS) were the first diseases tested (Cartier et A schematic representation of HSC GT showing the crucial steps of the process and its potential clinical applications: (1) HSPC are harvested from the mobilized peripheral blood or bone marrow of a patient and (2) cultured ex vivo in suitable conditions allowing maintenance or expansion of the rare cells with long-term repopulating potential, while they are subjected to gene transfer or gene editing. Emerging trials of HSC GT are testing its potential for delivering biotherapeutics in some cancer conditions (Escobar et al, , 2018, thus further expanding its application from the replacement of faulty inherited genes to cell and gene-based delivery of transgene products and the instruction of novel functions to the engineered HSC and/or their progeny. The gene-modified cells engraft in the bone marrow, where they self-renew potentially for the lifetime of the individual while giving rise to differentiating progeny along all hematopoietic lineages.…”

“…Because of the increasing confidence with its safety and therapeutic potential, clinical testing of LV-based HSC GT has now moved from confined testing in otherwise lethal conditions to broader application wherever HSCT is considered as treatment option, and patient inclusion criteria are expanding from the lack of a suitably matched HSC donor to the rationale of potentially providing better efficacy and/or improved safety over allogeneic transplantation. Emerging trials of HSC GT are testing its potential for delivering biotherapeutics in some cancer conditions (Escobar et al, , 2018, thus further expanding its application from the replacement of faulty inherited genes to cell and gene-based delivery of transgene products and the instruction of novel functions to the engineered HSC and/or their progeny.…”