Thorne SH, Negrin RS, Contag CH. Synergistic antitumor effects of immune cell-viral biotherapy. Science 2006;311:1780-4.

Most chemotherapy and radiotherapy regimens exploit a modest window of differential sensitivity between tumor cells and normal host tissue that prohibits dose escalation and limits effectiveness. Targeted biological therapies, therefore, hold tremendous potential for cancer treatment. In this paper, Thorne et al. combined immune effector cell populations that naturally migrate to tumors (cytokine-induced killer, or CIK cells) with an oncolytic virus (vaccinia) to achieve directed delivery to and regression of tumors in mouse models.

CIK cells are derived from blood or spleen mononuclear cells following a three-week ex vivo expansion with interferon-γ, interleukin-2, and CD3-specific antibody (OKT3). These cells migrate to tumor sites and exhibit non-major histocompatibility complex-restricted killing of tumor targets in vitro and in vivo. Vaccinia virus is a poxvirus that spends its entire lifecycle in the cytoplasm and induces profound cytopathic effects by inhibiting host protein synthesis, resulting in cell death. Modifying the virus by deleting the thymidine kinase gene and the vaccinia growth factor gene enhances tumor selectivity as viral replication becomes limited to dividing cells. The authors demonstrated that CIK cells infected with the modified vaccinia virus retained their ability to kill tumor targets in vitro. The virus remained dormant in these cells for 48-72 hours, roughly the same amount of time CIK cells take to localize to tumor sites. Whole body optical imaging confirmed that infected CIK cells trafficked efficiently to tumor sites in immune-competent and immune-deficient tumor-bearing mice, and delivered a pattern of viral biodistribution limited to the tumor sites with little virus detection in any other organ. The combination of CIK cells and modified vaccinia virus was highly efficacious and significantly extended the median survival in tumor-bearing mice compared with CIK cells or the modified virus alone. In fact, the combination therapy resulted in complete responses even in some cases of mice bearing CIK-resistant tumors.

This study puts forth a new paradigm for the delivery of cancer therapy. Thorne and colleagues used a population of hematopoietic cells, CIK cells, that naturally migrate to tumors to deliver a potent oncolytic virus. The CIK cells transported the virus deep within the tumors to provide a uniform distribution of infection. The viral infection in turn enhanced tumor cell killing by the CIK cells and significantly inhibited tumor growth in mice. Although each component of the therapy had been shown previously to have antitumor activity, their demonstrated synergy now offers the potential of a targeted biological therapy that may in combination prove to be much more effective. Many areas of study remain: Do dying cancer cells release a free virus that can infect other cells? If so, in what tissue? Vaccinia is known to infect a wide range of human tissue (yet not cause human disease), whereas murine tissue is relatively resistant to vaccinia infection. Is the antitumor effect compromised by concurrent or recently administered chemotherapy? The mechanism underlying the enhanced CIK cell antitumor activity following vaccinia infection is unclear; the specific subset within the broad population of CIK cells that transports and delivers the virus to tumor cells remains undefined. Ultimately, hematologists and transplant hematologists need to follow these types of strategies and collaborate with researchers in the field as the era of cellular therapy without hematopoietic cell transplantation for targeted cancer therapy is fast approaching.

Competing Interests

Dr. Lowsky indicated no relevant conflicts of interest.