Can Parvovirus B19 infection be naturally oncolytic: clinical findings raise such a possibility in leukaemic children.

Sir,

Oncogenic viruses are known for long but oncolytic viruses got highlighted recently. Tumour regression after natural measles virus infection/vaccinations has been observed in cases with leukaemia1. Currently, virotherapy of cancer using genetically engineered replication competent oncolytic viruses is a new biological weapon for cancers resistant to conventional anticancer therapies2. However, there are no reports on whether human parvovirus B19 (B19) has oncolytic property, though B19 is known to be associated with a wide range of clinical manifestations3.

Among many studies done by our group over the last one and a half decade on the implications of B19 infection in various clinical diseases data there were two studies involving children where mortality data and one year follow up data were available. Mortality patterns were assessed with respect to recent B19 infection based on the presence of anti-B19 IgM antibodies or B19 DNA in the serum.

The first pilot study comprised 35 children with haematological malignancies (newly diagnosed) mostly with ALL (acute lymphoblastic leukaemia) and six children (17.1%, 5 ALL, 1 non-Hodgkin lymphoma, NHL) were found to have B19 infection compared to one in 34 controls (P < 0.05)4. On comparing death rates among 29 B19 uninfected children, five children with haematological malignancies (17.1%) died in contrast to no deaths among six B19 infected group. The reason for this difference in mortalities remained unknown. A similar observation was found in case of a 13yr old male on treatment for CLL (chronic lymphocytic leukaemia) who was referred to our laboratory for investigation of unexplained prolonged chronic anaemia in March 2007. The child was positive for anti-B19 IgM antibodies by ELISA and B19 DNA by nested-PCR in the serum. Normally there are periods of remission and relapse in leukaemia but this child continued with remission for over one year and did not relapse (our unpublished data).

These findings on mortality (no deaths among B19 infected ALL patients and a case of CLL with prolonged remission) have raised an indication that natural B19 infection may have an unexplored oncolytic effect. Further the mechanism of such oncolysis may be due to apoptosis induced by B19 NS1 proteins5 or through toll like receptors (TLRs) activating nuclear factor kappa beta (NF-κB) transcription6. It may be noted here that though B19 virus primarily infects human erythroid lineage cells but it has also been detected in non-erythroid lineage cells in vivo, however, the mechanism of infection is not clear78. Thus B19 infected malignant blast cells may also be destroyed through apoptotic mechanism defraying deaths for a while9. It may also be noted here that the actual number of B19 infected cases could be more than that detected because B19 might remain in cryptic sites and viral titres might be low. Besides, children may fail to produce sufficient quantities of IgM antibodies owing to immune suppression due to malignancy and cytotoxic drugs. In another study10, B19 infection in children with ALL caused prolonged interruptions of chemotherapy and this may explain prolonged remission in the present case with CLL.

Our observations got further support after literature survey5671112131415 which revealed that rodent autonomous parvovirus H-1(H-1PV) that is non-pathogenic for human has strong intrinsic oncotropism, oncolytic activity and natural oncosuppressive effects against human tumours5. The first oncolytic preparation of H-1PV (ParvOryx) is undergoing phase I/IIa clinical trial in patients with primary or recurrent glioblastomamultiforme11. Recently it has been reported that H-1PV besides having an intrinsic oncolytic activity is able to enhance NK (natural killer) cell-mediated killing of tumour cells and can act as adjuvant and stimulate anti-tumour immune responses1213. More recently, H-1PV has been tried as a potential therapy against cervical and pancreatic carcinomas14. Besides naturally oncolytic measles virus15 several other oncolytic viruses like reovirus, herpes and vaccinia virus are in the late phase of clinical trials and may be combined with radio-or chemotherapy16.

These corroborative findings reported in literature further support our preliminary view that B19 virus may possibly be naturally oncolytic in leukemic children but because of a very small sample size and poor statistical significance these observations need to be interpreted with caution. Further investigations are warranted with large samples to verify this observation and to unveil a new dimension in the virotherapy of haematological malignancies specially ALL.