LOCAL INTERFERON-ALPHA DELIVERY INTO THE MYELOMA MICROENVIRONMENT BY GENE-ENGINEERED AUTOLOGOUS STEM CELL TRANSPLANTATION
Author(s): ,
Gabriele Antonarelli
Affiliations:
San Raffaele Telethon Institute for Gene Therapy,Milano,Italy
,
Adele Mucci
Affiliations:
San Raffaele Telethon Institute for Gene Therapy,Milano,Italy
,
Giulia Escobar
Affiliations:
San Raffaele Telethon Institute for Gene Therapy,Milano,Italy
,
Giacomo Desantis
Affiliations:
San Raffaele Telethon Institute for Gene Therapy,Milano,Italy
,
Francesco Maria Vittoria
Affiliations:
San Raffaele Telethon Institute for Gene Therapy,Milano,Italy
,
Alessia Capotondo
Affiliations:
San Raffaele Telethon Institute for Gene Therapy,Milano,Italy
,
Luigi Naldini
Affiliations:
San Raffaele Telethon Institute for Gene Therapy,Milano,Italy
,
Fabio Ciceri
Affiliations:
Hematology and Bone Marrow Transplant Unit,San Raffaele Hospital,Milano,Italy
Bernhard Gentner
Affiliations:
San Raffaele Telethon Institute for Gene Therapy,Milano,Italy;Hematology and Bone Marrow Transplant Unit,San Raffaele Hospital,Milano,Italy
EHA Library. Antonarelli G. Jun 15, 2019; 267495; S912
Gabriele Antonarelli
Gabriele Antonarelli
Contributions
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Abstract

Abstract: S912

Type: Oral Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:00 - 17:15

Location: Hall G106

Background
Multiple Myeloma (MM) is an incurable malignancy heralded by an immunosuppressive Tumor Microenvironment (TME). Therapeutic attempts aiming at reprogramming the TME and unleashing innate and adaptive immunity may synergize with current anti-MM drugs, deepen responses and ultimately prolong long-term survival. 

Aims
We developed an ex vivo Gene Therapy (GT) approach that locally delivers Interferon-alpha (IFNa) into the TME through the Tie2+ myeloid progeny of transplanted gene-modified Hematopoietic Stem and Progenitor Cells (HSPCs). 

Methods
Murine Lin- or human Cord Blood (huCB) HSPCs were transduced with lentiviral vectors (LV) expressing, respectively, murine or human IFNa under transcriptional control of the Tie2 promoter and post-transcriptional control by miR-126-3p thereby targeting IFNa expression to a subset of tumor-infiltrating monocytes. IFNa-LV-transduced or mock-transduced HSPC were transplanted into Vk*Myc transgenic mice after they have spontaneously developed a serum M-spike (immunocompetent mouse model) or into NSGW41 mice that were successively challenged with a luciferase+ MM.1S human myeloma cell line (human xenograft model). Myeloma disease progression was monitored by serum protein electrophoresis (Vk*Myc), whole body bioluminescence imaging (MM.1S) and bone marrow plasma cell burden at the endpoint. In the MM1.S model, IFNa-GT was combined with systemic Daratumumab (i.p.), Lenalidomide (i.p.) and Carfilzomib (i.v.) treatment.    

Results
In the spontaneous Vk*Myc mouse model of myeloma, Ifna GT halted myeloma progression (4 months PFS of 58.3% vs. 15.8% in control) and reduced mortality by >50%. Treatment response was associated with a higher proportion of CD8+ T cells in the BM and seen at donor cell chimerism as low as 4%. Mechanistic studies on the tumor microenvironment are ongoing. The NSGW41 xenograft model transplanted with huCB HSPCs allowed the development of a larger and more diverse human myeloid compartment compared to the classical NSG model. Even in the absence of adaptive immunity, IFNa-GT resulted in a significant reduction in BM myeloma burden (13.4+/-2.2% vs. 26.3+/-3.7% in mice transplanted with control huCB cells; n=19 vs. 18), independently confirmed by BLI. Interestingly, the IFNa-GT group showed an increased content of human CD33+ HLA-DR+ CD11c+ dendritic cells (including a pro-inflammatory SLAN+ subset) and increased levels of CD16 and HLA-DR expression on human myeloid cells within the myeloma-bearing BM, suggestive of myeloid cell reprogramming towards a more immune-stimulatory state. Moreover, IFNa-GT induced an upregulation of CD38 expression (on average 1.4 fold on myeloma cells). This provides a rationale for combining IFNa-GT with other anti-MM drugs. Indeed, the anti-MM effect of Daratumumab, Lenalidomide or Carfilzomib was enhanced by IFNa-GT, without excessive toxicity on the HSPC graft. 

Conclusion
Our studies conducted both in the immunocompetent Vk*Myc murine model as well as in the hematochimeric xenotransplantation setting demonstrate that IFNa-GT has robust anti-MM effect and may subvert the immunosuppressive MM TME, acting both on myeloma cells as well as on the immune infiltrate. A phase I/II dose-escalation study of IFNa-GT in patients with early-relapsed multiple myeloma has recently been approved and is starting accrual in March 2019.    

Session topic: 24. Gene therapy, cellular immunotherapy and vaccination - Biology & Translational Res

Keyword(s): Immunotherapy, Interferon alpha, Multiple myeloma

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