Human mesenchymal stromal cells deliver systemic oncolytic measles virus to treat acute lymphoblastic leukemia in the presence of humoral immunity

Abstract

Key Points• Human BM-MSCs can be used to successfully deliver systemic oncolytic measles virotherapy to ALL tumor targets.• This approach permits circumvention of preexisting anti-measles humoral immunity and enhanced therapeutic outcomes.Clinical trials of oncolytic attenuated measles virus (MV) are ongoing, but successful systemic delivery in immune individuals remains a major challenge. We demonstrated high-titer anti-MV antibody in 16 adults with acute lymphoblastic leukemia (ALL) following treatments including numerous immunosuppressive drugs. To resolve this challenge, human bone marrow-derived mesenchymal stromal cells (BM-MSCs) were used to efficiently deliver MV in a systemic xenograft model of precursor B-lineage-ALL. BM-MSCs were successfully loaded with MV ex vivo, and MV was amplified intracellularly, without toxicity. Live cell confocal imaging demonstrated a viral hand-off between BM-MSCs and ALL targets in the presence of antibody. In a murine model of disseminated ALL, successful MV treatment (judged by bioluminescence quantification and survival) was completely abrogated by passive immunization with high-titer human anti-MV antibody. Importantly, no such abrogation was seen in immunized mice receiving MV delivered by BM-MSCs. These data support the use of BM-MSCs as cellular carriers for MV in patients with ALL. (Blood. 2014;123(9):1327-1335) IntroductionAdult acute lymphoblastic leukemia (ALL) is an aggressive hematological malignancy with complete remission rates following initial induction therapy of 85% to 95%. [1][2][3][4][5][6][7][8] Despite cycles of combined immunosuppressive and myelosuppressive chemotherapeutics, longterm survival is achieved in fewer than half of adults, 9 and few patients with relapsed disease survive. 10 The ability to quantify and monitor minimal residual disease in the majority of patients with ALL, provides a basis-already recognized by the regulatory authorities-for early intervention with novel therapeutics prior to overt disease relapse, 11 which would be the optimal setting for novel biological therapies.Oncolytic viruses (OVs) preferentially infect and lyse transformed cells, leaving normal cells relatively unharmed. They lack crossresistance with existing therapies, and the acceptable safety profile of OVs has been demonstrated in numerous trials. [12][13][14][15][16] Vaccine-strain live, attenuated MV (MV-Edm) has shown tumor-specific replication and antitumor activity in a range of malignancies, [17][18][19][20][21][22][23][24][25][26][27][28][29][30] with published phase 1 clinical trials showing safety and some therapeutic promise in cutaneous T-cell lymphoma 31 and ovarian cancer. 32 Sophisticated manipulations of the vaccine MV genome can aid tumor targeting [33][34][35][36][37] and assist with in vivo tracking. 21,38,39 Despite this, the necessity to shield MV from neutralizing antibody during systemic delivery has not been appropriately addressed 40,41 but is likely to preclude repeat dosing regimes and impact adversely on therapy.There has been in...

UV-inactivated HSV-1 potently activates NK cell killing of leukemic cells

“…15,36,37 Herein we show that HSV-1, both live and UV light-inactivated, activates NK cells to kill leukemic cell lines and primary AML samples. We also show for the first time that UV-HSV-1 is 100-to 1000-fold more potent than UV-inactivated VSV (Rhabdoviridae), Reovirus (Reoviridae), or Adenovirus (Adenoviridae) in promoting PBMC-induced cytolysis of leukemia targets.…”

Oncolytic virotherapy for ALL: MSCs to the rescue

“…6 Castleton et al use bone marrow-derived MSCs as carriers (effectively ALL-targeting producer cells) of the oncolytic MV to circumvent the anti-measles humoral immunity found in most patients which does not seem to be abrogated by their prior chemotherapy. 1 MSCs are an attractive cell carrier as they are easily isolated from a bone marrow aspirate, readily ex vivo-expanded under good manufacturing practice conditions, and may be infused across HLA barriers. The hundreds of clinical trials worldwide over the last 2 decades persuasively support the safety of these cells for clinical applications.…”

Trial Watch—Oncolytic viruses and cancer therapy

“…1,2,30 For instances, several populations of tumor-infiltrating cells have been engineered as vehicles to deliver viral particles within neoplastic lesions. [132][133][134][135][136][137][138] Oncolytic virotherapy has also been questioned owing to threats that are intrinsically associated with the use of replicating viral particles, especially in weak and sometimes immunosuppressed individuals like cancer patients. [139][140][141][142][143][144][145] Nevertheless, multiple oncolytic viruses have been associated with remarkable rates of objective and durable responses in clinical studies, especially when they were used in combination with other chemo-or immunotherapeutic agents.…”