H U M A N G E N E THERAPY 2:1-2 (1991) Mary Ann Liebert, Inc., Publishers
EDITORIAL Cautious O p t i m i s m
T H E operative w o r d s are "cautious optimism." They apply to the initial human gene therapy trial that began on September 14,1990; they apply to the entire field of human gene therapy; and they apply to this journal which, with this issue, begins its second year of publication. The first gene therapy patient, a four-year-old girl suffering from adenosine deaminase ( A D A ) deficiency, continues to do well. She has had three infusions of autologous gene-corrected T cells. Her T-cell count is n o w in the normal range for the first time in her life and gene-corrected T cells can be isolated directly from her blood. Her parents are delighted because she has never gone so long without a cold or other illness. Truly reasons for optimism. But caution is necessary. W e are all aware of new treatments that appear to be successful initially, only to prove of little value after more clinical experience. Several years ago transfusions with irradiated red blood cells (as a source ofthe missing enzyme A D A ) appeared to be an effective therapy for some patients with A D A deficiency. Unfortunately, patients w h o were initially responsive became refractory and n o w the procedure is seldom used. Will history repeat itself for patients w h o receive genecorrected T cells? In theory, no, because these are the patient's o w n cells and they presumably fill an unoccupied niche in the hematopoietic system. But only time will resolve whether or not the present encouraging results persist. Furthermore, there is no evidence except for the parents' anecdotal observations that the patient herself has been helped at all. Better blood values are one thing; true clinical improvement is quite another. W e must wait, with cautious optimism, to see. The infant field of human gene therapy also appears healthy. B y most criteria there has been spectacular success over the past year. Certainly it is encouraging that the N2/TIL human gene transfer clinical protocol (started in M a y , 1989) and the A D A human gene therapy protocol (discussed above) are doing so well. The TNF/TIL human gene therapy clinical protocol for treatment of malignant melanoma (Hum. Gene Ther. 1, 441480) received final F D A approval on January 8, 1991, and is about to begin. Equally encouraging are the number of other clinical programs around this country and the world that are n o w initiating human gene transfer/therapy protocols. T w o gene marker clinical protocols received approval with stipulations at the November 30, 1990, H u m a n Gene Therapy Subcommittee and will be considered at the February 4,1991, R A C meeting. These were a
1
study in pediatric acute myelogenous leukemia at St. Jude Children's Research Hospital, and a study marking TIL (similar to the N2/TIL protocol) at University of Pittsburgh. T w o additional protocols were deferred pending submission of additional preclinical data (the Subcommittee and the R A C have always required that high standards be met before approval is given). These were a marking protocol in adult leukemia from the University of Wisconsin and a marking protocol in pediatric neuroblastoma from St. Jude. Several other protocols are being prepared in this country. The first gene therapy protocol in Europe was submitted in Italy late in 1990 and is n o w under review. Various gene transfer/therapy protocols are being prepared in a number of countries including Canada, France, and the Netherlands. Thus, by virtue of sheer numbers the field of gene therapy appears to be advancing rapidly. Another measure of success is the financial support that a field receives. The N I H , and particularly the National Heart, Lung, and Blood Institute, has targeted gene therapy as one of several key areas to emphasize in the 1990s. A number of biotech companies are focusing on gene therapy, and n o w it appears that several of the major pharmaceutical firms are planning to begin research and development programs in gene therapy. Thus, a major effort by federal, university, and private resources is beginning that should result in significant advances in this young field. But caution is necessary. Hope and optimism do not guarantee success. The fact is that not a single patient has yet been proven to be helped by gene therapy. The present protocols are extremely costly and high tech. There remain significant biological as well as technical hurdles to overcome before gene therapy will be a useful clinical (and, therefore, commercially viable) procedure (e.g., see H u m . Gene Ther. 1, 227-228). Without major drug company involvement, gene therapy cannot receive the funding it needs to be developed into an inexpensive low-tech (i.e., inject-a-gene) procedure. Pharmaceutical companies are understandably reluctant to invest the millions of dollars required without substantial evidence that there will be a commercial payoff in the end. Substantial evidence does not yet exist. A n d our journal H u m a n Gene Therapy certainly appears to be off to an excellent start. A s stated in m y initial editorial (Hum. Gene Ther. 1,1): In summary, the two distinguishing characteristics of Hum a n Gene Therapy will be: (i) attention to all aspects of this
ANDERSON specific field, including the broader social issues; (ii) a resource for current information as well as a repository for future reference.
But again, caution is necessary. H u m a n Gene Therapy began as a unique experiment and, therefore, had a certain novelty. N o w w e must prove ourselves as a respected peer-reviewed journal over the long haul. The critical element for a scientific Both of these objectives are being fulfilled. We are publishing journal is the quality of its scientific papers. Only when w e are important scientific papers, but equally important is the fact that able to maintain a consistent level of high-quality papers over an more papers on the ethical, legal, regulatory, and social aspects extended period of time will w e consider that this journal is fully of human gene therapy were published here last year than in all a success. "Cautious optimism" remain the operative words for the first other journals combined. A n d nowhere else in a single location can one find the clinical protocols, the minutes of the H u m a n gene therapy trial, for gene therapy as a field, and for our Gene Therapy Subcommittee and the Recombinant D N A Advi- journal. But the stakes in terms of relief of h u m a n suffering are sory Committee meetings, important regulatory papers (e.g., too high to become complacent. The emphasis should remain on the R A C ' s revised Points to Consider; the F D A ' s o w n Points to the word cautious, even if w e feel enormously optimistic. There Consider, as soon as they are finalized, together with c o m m e n - is a long road ahead still to be traveled. tary), as well as policy documents from various sources on human gene therapy. A n d the publisher tells m e that by their criteria (subscriptions, impact, early inclusion in citation indiDr. W . French Anderson ces, etc.) the journal is successful. Editor-in-Chief
EDITORIAL Cautious O p t i m i s m
T H E operative w o r d s are "cautious optimism." They apply to the initial human gene therapy trial that began on September 14,1990; they apply to the entire field of human gene therapy; and they apply to this journal which, with this issue, begins its second year of publication. The first gene therapy patient, a four-year-old girl suffering from adenosine deaminase ( A D A ) deficiency, continues to do well. She has had three infusions of autologous gene-corrected T cells. Her T-cell count is n o w in the normal range for the first time in her life and gene-corrected T cells can be isolated directly from her blood. Her parents are delighted because she has never gone so long without a cold or other illness. Truly reasons for optimism. But caution is necessary. W e are all aware of new treatments that appear to be successful initially, only to prove of little value after more clinical experience. Several years ago transfusions with irradiated red blood cells (as a source ofthe missing enzyme A D A ) appeared to be an effective therapy for some patients with A D A deficiency. Unfortunately, patients w h o were initially responsive became refractory and n o w the procedure is seldom used. Will history repeat itself for patients w h o receive genecorrected T cells? In theory, no, because these are the patient's o w n cells and they presumably fill an unoccupied niche in the hematopoietic system. But only time will resolve whether or not the present encouraging results persist. Furthermore, there is no evidence except for the parents' anecdotal observations that the patient herself has been helped at all. Better blood values are one thing; true clinical improvement is quite another. W e must wait, with cautious optimism, to see. The infant field of human gene therapy also appears healthy. B y most criteria there has been spectacular success over the past year. Certainly it is encouraging that the N2/TIL human gene transfer clinical protocol (started in M a y , 1989) and the A D A human gene therapy protocol (discussed above) are doing so well. The TNF/TIL human gene therapy clinical protocol for treatment of malignant melanoma (Hum. Gene Ther. 1, 441480) received final F D A approval on January 8, 1991, and is about to begin. Equally encouraging are the number of other clinical programs around this country and the world that are n o w initiating human gene transfer/therapy protocols. T w o gene marker clinical protocols received approval with stipulations at the November 30, 1990, H u m a n Gene Therapy Subcommittee and will be considered at the February 4,1991, R A C meeting. These were a
1
study in pediatric acute myelogenous leukemia at St. Jude Children's Research Hospital, and a study marking TIL (similar to the N2/TIL protocol) at University of Pittsburgh. T w o additional protocols were deferred pending submission of additional preclinical data (the Subcommittee and the R A C have always required that high standards be met before approval is given). These were a marking protocol in adult leukemia from the University of Wisconsin and a marking protocol in pediatric neuroblastoma from St. Jude. Several other protocols are being prepared in this country. The first gene therapy protocol in Europe was submitted in Italy late in 1990 and is n o w under review. Various gene transfer/therapy protocols are being prepared in a number of countries including Canada, France, and the Netherlands. Thus, by virtue of sheer numbers the field of gene therapy appears to be advancing rapidly. Another measure of success is the financial support that a field receives. The N I H , and particularly the National Heart, Lung, and Blood Institute, has targeted gene therapy as one of several key areas to emphasize in the 1990s. A number of biotech companies are focusing on gene therapy, and n o w it appears that several of the major pharmaceutical firms are planning to begin research and development programs in gene therapy. Thus, a major effort by federal, university, and private resources is beginning that should result in significant advances in this young field. But caution is necessary. Hope and optimism do not guarantee success. The fact is that not a single patient has yet been proven to be helped by gene therapy. The present protocols are extremely costly and high tech. There remain significant biological as well as technical hurdles to overcome before gene therapy will be a useful clinical (and, therefore, commercially viable) procedure (e.g., see H u m . Gene Ther. 1, 227-228). Without major drug company involvement, gene therapy cannot receive the funding it needs to be developed into an inexpensive low-tech (i.e., inject-a-gene) procedure. Pharmaceutical companies are understandably reluctant to invest the millions of dollars required without substantial evidence that there will be a commercial payoff in the end. Substantial evidence does not yet exist. A n d our journal H u m a n Gene Therapy certainly appears to be off to an excellent start. A s stated in m y initial editorial (Hum. Gene Ther. 1,1): In summary, the two distinguishing characteristics of Hum a n Gene Therapy will be: (i) attention to all aspects of this
ANDERSON specific field, including the broader social issues; (ii) a resource for current information as well as a repository for future reference.
But again, caution is necessary. H u m a n Gene Therapy began as a unique experiment and, therefore, had a certain novelty. N o w w e must prove ourselves as a respected peer-reviewed journal over the long haul. The critical element for a scientific Both of these objectives are being fulfilled. We are publishing journal is the quality of its scientific papers. Only when w e are important scientific papers, but equally important is the fact that able to maintain a consistent level of high-quality papers over an more papers on the ethical, legal, regulatory, and social aspects extended period of time will w e consider that this journal is fully of human gene therapy were published here last year than in all a success. "Cautious optimism" remain the operative words for the first other journals combined. A n d nowhere else in a single location can one find the clinical protocols, the minutes of the H u m a n gene therapy trial, for gene therapy as a field, and for our Gene Therapy Subcommittee and the Recombinant D N A Advi- journal. But the stakes in terms of relief of h u m a n suffering are sory Committee meetings, important regulatory papers (e.g., too high to become complacent. The emphasis should remain on the R A C ' s revised Points to Consider; the F D A ' s o w n Points to the word cautious, even if w e feel enormously optimistic. There Consider, as soon as they are finalized, together with c o m m e n - is a long road ahead still to be traveled. tary), as well as policy documents from various sources on human gene therapy. A n d the publisher tells m e that by their criteria (subscriptions, impact, early inclusion in citation indiDr. W . French Anderson ces, etc.) the journal is successful. Editor-in-Chief
