Oncolytic Measles Virus MV-NIS Controls Relapsed ALL Patient-Derived Xenografts

The prognosis of children with relapsed and refractory ALL is poor. CAR T cells, bispecific antibodies and immunological checkpoint inhibitors hold great promise, but their long-term efficacy has yet to be proven. Hence there is a need for additional novel therapies. We and others have shown that oncolytic measles virus (OMV) are preclinically efficacious in non-refractory ALL. It is yet unknown whether relapsed and refractory ALL are susceptible to OMV. We thus investigated the preclinical efficacy of MV-NIS, the OMV used in clinical trials for solid tumors, against relapsed and refractory ALL.

First, ALL cell lines insensitive to chemotherapy were treated with MV-NIS. Despite their chemoresistance these ALL cells were sensitive to MV-NIS in vitro . Next, ALL xenografts derived at the time of relapse from patients that eventually succumbed to their relapse were treated in NSG mice. We simulated the situation of candidate patients, i.e. the many children with ALL that have lost immunity against MV and who will develop neutralizing antibodies after initial injection of OMV. Thus, mice - which do not have antibodies against measles - received just one injection of MV-NIS. Virus was applied only after the leukemic burden was high, similar to the situation that will be encountered in patients. Whereas all untreated mice rapidly died, corresponding to the aggressiveness and extent of the disease, peripheral blast counts in the treated mice quickly decreased, leading to long-term survival of the mice. Eventually, late recurrences developed in the mice. This made it possible to investigate the hitherto not addressed in vivo development of resistance of ALL cells to OMV. Counter to expectation, replicating OMV were still dectable in situ in many blasts at recurrence. Intriguingly, while cell death or syncytium formation, the defining cytopathic effect of measles virus, were not evident in blasts with replicating virus, viral particles recovered from the recurrences showed marked lytic activity against Vero cells in vitro . This strongly suggests resistance mechanisms within the blasts rather than oncolysis-attenuating mutations within the viral genome. Sequencing data will be presented that compare the initially responsive to the eventually resistant ALL xenograft cells and the initial OMVs to the OMVs isolated from the recurrences. This will define candidate genes for susceptibility and resistance of ALL to MV-NIS.

This data shows that relapsed and chemorefractory ALL is susceptible to MV-NIS. In addition, it will provide biomarkers to choose suitable patients and to delineate approaches to circumvent resistance against OMV.