Viral Therapy of Human Cancers PDF

Preface

Could viruses contribute to the cure of cancer? Viruses certainly contributed to the cause of cancer. Retroviruses transduced cellular proto-oncogenes and converted them into oncogenes. Certain DNA viruses knock out the tumor suppressor gene product proteins of p53 and Rb and counteract early apoptotic death of the infected cell, thus eliminating a self-defensive reaction of the infected host, in which these virions or at least their genomes will persist. The infected cells assume transformed or malignant pheno- and genotypes, gain ‘‘immortality'' and grow as cancers. On the other hand, some naturally acquired virus infections induced remissions in tumor-bearing patients. There are rare but well documented and published records of various human malignancies, more leukemias and lymphomas than other types of cancers, yielding to a natural viral infection and regressing without relapse. In the laboratory, mice and other experimental animals are readily cured of their cancers, ascitic tumors in particular, by direct inoculation of these tumors, or by infection of the animals with some selected viruses that are not pathogenic in these hosts. These ‘‘oncolytic viruses'' readily kill tissue cultures or xenografts of human cancers. In clinical trials, be as simplistic as letting patients repeatedly drink or intranasally inhale or receive as an enema untitrated veterinary virus preparations, or as sophisticated as the intratumoral injections of a genetically engineered virus, tantalizing, rare, temporary remissions of cancers occur and are lost to relapses. Long stabilizations of the disease are more commonly recorded and are readily attributed to the viral intervention, disregarding that some advanced tumors can assume a Gompertzian growth curve and slow down their growth rate on their own. Decades go by, but not one particular virus emerges as the ideal oncolytic agent for human tumors.

In melanoma, there is a strong claim that oncolysates prepared with Newcastle disease virus eliminated subclinical microscopic disease left behind after surgical removal of gross tumors. Because the Cassel-Murray clinical trial was evaluated against historical controls and was not prospectively randomized, it is not readily accepted as valid. Even though the trial was impeccably carried out for almost two decades, the academic institution (Emory University, Atlanta, GA) keeps accurate records of its patients and tumor-free patients are alive, this claim of successful virotherapy of a highly malignant human cancer is often ignored and dismissed. However, we accepted the curative value of the MOPP regimen for Hodgkin's disease and that of the first cis-platin, bleomycin and vinblastine protocols for testicular carcinoma without prospectively randomized trials. If it is true that microscopic subclinical cancer can be eradicated by a virus, then it is also possible that resident apathogenic viral flora of the human host (parvoviruses; reoviruses; and as yet undiscovered other viruses) can eliminate incipient newly emerging tumors. Further, if this really could happen, some anti-tumoral immunity should remain in these individuals. We cite not only the surveillance by innate NK cells that kill virally infected cells and tumor cells and respond first to immunizations of patients with viral oncolysates, but also the immune T cells, which arise after the inception of a tumor. If one of us could document immune T memory cells specifically reactive to tumor-associated antigens in a healthy and tumorfree individual who never had any documented cancer before, would this finding be acceptable as a proof for the rejection of an incipient tumor in that individual? It would require a series of additional documentation to establish just how that incipient tumor was rejected; viral attack on that tumor would be one of the possible means of its rejection.

In this volume, virologists of the old school meet with the new generation of molecular virologists. Together we try to decipher the controversies embedded in the intricate processes of viral oncolysis, as this discipline of treatment for cancer is applied in preclinical and clinical trials. We are comparing the efficacy of naturally oncolytic and genetically engineered viruses. Gene therapy of cancer has not been reviewed, however, it has not been ignored! It is frequently referred to in this volume. The new generation of virologists persuing the virotherapy of human cancer forms a nicely knit cooperative group. They meet, confer and publish together. Here we list just a few of their recent conferences to guide the reader to early abstracts and full reports. A. Cid-Arregui (Heidelberg, Germany) and A. Garcı´a-Carranca´ (Ciudad Mexico, Mexico) edited the volume ‘‘Viral Vectors: Basic Science and Gene Therapy'' published by Bio-Techniques/ Eaton (Natick, MA) in 2000. In that volume from adenoviruses to vesicular stomatitis virus all genetically engineered viral agents useful for the viral therapy of cancer are elaborated on. A conference on ‘‘Replicating Vectors for Gene Therapy'' took place in Rochester, Minnesota on October 5-7, 2001. This conference was organized by the Mayo Clinic and its abstracts are printed in Gene Therapy volume 8, Supplement 1, 2001. The abstracts of the ‘‘Eleventh International Conference on Gene Therapy of Cancer'' was held on 12-14 December, 2002 in San Diego, California; its abstracts are printed in a special extra volume of Cancer Gene Therapy 2003; 10: S1-S44. Papers on naturally oncolytic and genetically engineered viral vectors were presented at these conferences. Finally, the conference entitled ‘‘Oncolytic Viruses as Cancer Therapeutics'' was held on March 26-30, 2003 in Banff, Canada, organized by the Ottawa Regional Cancer Centre (www.orcc.on.ca). There, a most spectacular array of presentations took place with the take home message that we do have a new and working weapon against cancer in the form of naturally oncolytic and/or genetically engineered viruses. Will viral therapy of human cancers match or surpass the efficacy of chemoradiotherapy or that of the new biological therapeuticals: gene therapy (T. Wasil and A. Buchbinder), ribozymes (Louise Wright and P. Kearney), or antisense oligonucleotides ( B.P. Monia, J. Holmlund and F.A. Dorr) as reviewed in Cancer Investigation (Marcel Dekker) volumes 18-9, 2000-1. Is viral therapy of human cancers a collaborator or a competitor of tyrosine kinase inhibitors targeting oncogene cascades or that of cancer vaccines or monoclonal antibodies/immunotoxins? Would sensational announcements of success with virotherapy of cancer (T. Pawlik and K. Tanabe inducing death of colon carcinoma cells with Herpes simplex virus mutant rRp450 and using it with cyclophosphamide and ganciclovir for the treatment of liver metastases) translate for therapy and withstand the tear and wear of late relapses (Oncology News International, June, 2000).

It is a privilege for us to serve as editors of a volume on virotherapy of cancer. In this volume, we present virotherapy of cancer in context, that is, how it is related to work done along these lines decades ago and how it is comparable with other biological therapeuticals now in clinical trials. The abundance of choices is overwhelming. Close to innumerable adenoviral vectors populate the field. We could have catalogued or tabulated them giving each item one line. Instead, one of us (JGS) condensed each of them in a sentence or two with a reference. Enough information is given to the reader to locate the viral vector of interest in the computer or in the library. There is a saying in medical oncology: ‘‘if a tumor category is being treated with more than five regimens, that means none of them is working''. Hopefully, this dictum is not applicable to the rapidly proliferating adenoviral vectors. Each of them is the result of superb basic knowledge of tumor cell biology and congenial thinking; each of them deserved to be cited.

One of us (JGS) expresses his gratitude to Dr. Robert W. Simpson, emeritus professor of virology, The State University, Rutgers, The Waksman Institute, New Brunswick and Piscataway, New Jersey, and to Dr. H. David Kay, virologist, immunologist and patent attorney formerly affiliated with The University of Texas M. D. Anderson Hospital, Houston, Texas, and with The University Medical School, Omaha, Nebraska for reading and criticizing the JGS manuscripts.

While this volume was edited, The U.S.A. Department of Agriculture launched an investigation on all Newcastle disease virus strains used for research and vaccination to find out if these virus strains posed any biohazard to wild and domesticated birds, especially poultry, and to human beings. One of us (JCH) had to turn his full attention toward cloning and sequencing part of the genome of the 73T Newcastle disease virus strain with which we prepare our viral oncolysates for immunization of patients. However, the virus turned out to be not viscerotropic and it poses no biohazards in the human community or in the ecosystems in which we live. Our work at Emory University (Atlanta, GA) with this virus may continue unimpeded.

We regret the delays this publication had to sustain. Nevertheless, we proudly present to the readers some magnificent articles on viral oncolysis and are very grateful to the authors for their contributions. In the chapter on biological therapy of cancer, one of us (JGS) frequently mentions (in parentheses) drug companies and laboratories sponsoring research on this subject matter. This is done to assist the interested reader to locate better the source of information and facilitate making contact with the manufacturer of a new investigational product. Here we, the editors of this volume, explicitly declare that neither one of us received any monetary rewards or presents from any one of the cited (or non-cited) drug companies or research laboratories.

The contributing authors were given unrestricted liberty as to the construction of their chapters and as to their choices for literature citations. Since we could not engage Dr. Patrick Lee for a reovirus chapter, we asked Drs. M. Bergmann and T. Muster to include a review of oncolytic reoviruses into their chapter. Who could have contributed better than the P.W.K Lee team [1]? After CRC Press and Marcel Dekker publishers united, we had the good fortune to have the assignment of Ms Kathryn Phillips of Maryland Composition as project manager to take charge of the accelerated publication of this volume. Ms Phillips removed all elements of stagnation and acted with care and expertise. We wish to express our gratitude for her efficient interventions. We hope that we have rendered a useful service for those who work in the laboratories or conduct clinical research on the virotherapy of human cancers; to the medical oncologists in practice; and to those patients who are in need of innovative new treatment modalities.