Cancer Gene Therapy at the Crossroads

GETTING THE VECTOR RIGHT

Beyond advancements in cancer biology and immunology, steady progress in vector design promises to improve prospects. One of the main limitations of viral vectors is their inherent immunogenicity. Immune responses have been shown to be directed against the vector, against the expressed transgene, and as a bystander effect triggered by inflammation and cell death. While these effects present severe constraints for the therapy of many congenital diseases, this may actually serve as a major benefit for many applications in cancer gene therapy.

For example, where investigators approached advanced lung and oropharyngeal cancer by injecting retroviral or adenoviral vectors encoding native p53,⁷ clinical trials have been unexpectedly successful even though only a fraction of the tumor cells express a corrected p53 gene. The excess apoptotic cells in tumor biopsies indicate a bystander effect, and it is almost certain that induction of p53-independent antitumor immunity is responsible for much of the observed responses. Introgen Therapeutics is currently testing this strategy in Phase III trials for recurrent and refractory squamous cell carcinoma of the head and neck.

For stable gene expression, replication-defective oncoretroviruses have been the vector of choice. A critical issue facing the field is that retroviruses can cause insertional mutagenesis, which led to leukemia in the case of hematopoietic stem-cell therapy for X-linked SCID.¹ Several conditions may have inadvertently set up a perfect storm here: The γc gene itself may be oncogenic; the massive expansion of gene-corrected cells in vivo may select for damaged cells; and stem cells themselves may be more susceptible to insertional mutagenesis.

Frederic Bushman and colleagues have shown that lentiviruses such as HIV exhibit integration patterns that are distinct from C-type viruses, such as the Moloney retrovirus used in the X-SCID trials.⁸ Given that the natural history of HIV-1 lentiviral infection does not lead to T-cell leukemia despite billions of integration events in vivo, lentiviruses may be safer vectors in this respect. We have recently completed the first lentiviral gene-transfer protocol at the University of Pennsylvania in collaboration with ViRxSys.

In this adoptive transfer protocol (OBA/RAC protocol #0107-488), five patients with late-stage HIV infection were given a single infusion of lentiviral transduced T cells, and to date, we have observed safety and long-term lentiviral gene transfer. The cells from these patients afford the opportunity to investigate vector insertion sites. Studies underway in the Bushman laboratory currently suggest that the vector inserts in a fashion indistinguishable from wild type HIV-1. If lentiviruses continue to have a favorable safety profile, then it is likely they will have a large and perhaps revolutionary role in cancer gene therapy.

CHALLENGES AND PAYOFF

© 2005 Humana Press

A MEDLINE search through English language literature reveals this picture of 147 published gene therapy clinical trials by strategy. The immunotherapy wedge is further subcharacterized. (Modified with permission from R.J. Korst and R.G. Crystal, from Cancer Gene Therapy, D.T. Curiel, J. Douglas (eds) Totowa, NJ: Humana Press, 2005, p. 451.)

Several issues will have a crucial bearing on the success or failure of cancer gene therapy: The clinical trials are expensive, requiring in excess of $1 million for a Phase I pilot trial. This alone creates funding shortfalls for the field. Moreover, in contrast to a few years ago when pilot biologic trials could be carried out by academics with NIH funding, today a pilot gene-therapy trial requires large teams of scientists, clinicians, lawyers, and involvement with biotechnology companies to navigate the regulatory environments in the United States and Europe. Thus, rapid pilot trials are no longer possible, and one must proceed to clinical experiments only after considerable deliberation.

Despite funding as well as scientific challenges, I believe it is likely that therapeutic cancer vaccines employing gene therapy to enhance immunogenicity will be FDA-approved modalities in this decade. Moreover, some of these genetically engineered vaccines may well turn out to be blockbuster drugs.

Many immunotherapies work as cytostatic agents as well as cytotoxic agents. To the extent that the cytostatic effects dominate in prolonging tumor survival, treatment is continued on an indefinite basis, similar to signal transduction inhibitors such as Gleevec. Recent studies also have shown that unlike in the case of prophylactic vaccination where antigen is cleared, immune memory is not induced in states of persistent antigen. Thus, in therapeutic cancer settings, it may be necessary to give induction and maintenance therapy with genetically engineered cancer vaccines.

Biologic therapies with monoclonal antibodies such as Herceptin and Rituxin share many features that cancer vaccines are anticipated to exhibit: They require chronic administration; they complement the activity of conventional cytotoxic agents, and they are relatively free of toxicity. Even cancer vaccines targeted at relatively rare tumors such as follicular lymphoma can have a major market for the pharmaceutical industry, as the patients may require lifelong therapy to maintain effective antitumor immunity.

In addition to the use of gene therapies to induce active vaccine responses, it is likely that passive adoptive transfer therapies with genetically engineered T cells and other lymphocyte subsets will come of age. As mentioned, potent antitumor immune effects are associated with allogeneic marrow transplantation. In principle, lentiviral vector engineering should make it possible to duplicate these effects in the autologous setting.⁹ A pilot trial to test lentiviral engineered T cells that have been retargeted to leukemia antigens is currently in preclinical development here. If lentiviral-vector engineering of T cells continues to live up to the promise that we've observed in the initial clinical study, then this will become a practical and powerful technology in the near future.

Carl June is director of translational research at the Abramson Cancer Center at the University of Pennsylvania, and an investigator at the Abramson Family Cancer Research Institute.

He can be contacted at cjune@mail.med.upenn.edu.