CANCER VACCINES AND GENE THERAPY CURRENT CLINICAL STATUS
 

By.
Professor A G Dalgleish MD,
Professor of Oncology and Visiting Professor at the Institute of Cancer Research
St. George's Hospital Medical School
Cranmer Terrace
LONDON
SW170RE

 

Introduction

The history of cancer vaccines is closely related to the difficulties encountered in the treatment of advanced melanoma, is notoriously resistant to chemotherapy and radiotherapy, and the best form of treatment is surgical excision. Unfortunately the disease may spread and recur, a feature which is more Iikely with the depth and invasion of the primary tumour and the involvement of draining lymph nodes. The idea that stimulating the immune system could lead to a new way of treating melanoma is, paradoxically, older in concept that either chemotherapy or radiotherapy. The first well documented evidence that treating patients with immune stimulants could lead to regression of established tumours was shown by William Coley, a New York based surgeon, who noticed the spontaneous resolution of tumours following severe infection. He therefore went on to develop what he presumed to be the active component of the infections which lead to the regression of tumours and these became known as "Coley's toxins" which were essentially bacterial cell wall preparations. The fact that spontaneous resolution of melanoma was and is still being seen, albeit at a relatively uncommon rate, underscored the suitability for the development of immunological approaches to the treatment of melanoma.
 

Non-specific therapies

Non-specific therapies such as the BCG vaccine, Interferon and Interleukin 2 have all been tried in a variety of tumours and in all of these studies melanoma features as one of the most responsive. Unfortunately, with the exception of BCG which when injected into local lesions give rise to a partial or complete response in around 5O~o of cases, the response to Interferon and Interleukin remains relatively poor at about 2O%. Nevertheless, the fact that some of the patients that do respond to Interferon and Interleukin 2 go on to have prolonged responses has encouraged the further development of tumour immunology.
 

Cancer vaccines

There have been a number of studies world-wide on the use of a variety of vaccine preparations for the treatment of melanoma. Very encouraging Phase II studies have lead to commencement of a number of randomised Phase III studies. These are mainly occurring in patients with Stage III disease, which means patients with deep primaries or involved lymph nodes who have no evidence of disease following excision. The fact that tumours which have been completely excised may benefit from vaccination approaches is underscored by a myriad of animal experiments as well as studies on patients with Stage IV or metastatic disease where the response to vaccination is much better when the bulk of the disease can be completely removed or at least debulked. The most important vaccines which are under further development to date are:

1: The MCV or melanoma cell vaccine of Dr Morton at the John Wayne Cancer Institute. This vaccine consists of 3 highly antigenic cells given with BCG to patients with Stage III and Stage IV cancer. Although over 1,00 (?amt) patients have received this treatment, it has only recently undergone randomisation and it will take 2-3 years before the full effect of this vaccine is known from these studies. However, the survival curve in case controlled studies and analyses with historical and databases elsewhere strongly suggests that the vaccine can enhance 5 year survivals by at least 3-4 fold and in selected cases, such as those patients with pulmonary metastases which have been excised, considerably more so.

2: The major antigen thought to be present on these cells is a ganglioside called GM2 and immune responses to this correlate very well with the survivors of the MCV vaccine. Dr Livingstone and colleagues at the Sloane-Kettering purified this ganglioside and conducted a randomised Phase III study on patients with Stage III disease i.e.: resected lymph nodes. Although this study failed to achieve statistical significance with regards to the fact that patients who received the vaccine survived the longest, further analysis suggested that it was the immune system that correlated with survival as 6 patients who did not get the active vaccine had already developed strong antibody responses to the ganglioside whereas only two thirds of the patients who got the vaccine developed antibody responses. If the data was reinterpreted as to survival relative to the immune response, whether or not induced naturally or by the vaccine, then the survival advantage was highly significant. This study has lead to a much larger randomised Phase III study which is being conducted in the U S., Australia and soon, we hope, the United Kingdom. The vaccine, 'Megavax' has been mixed with a much better adjuvant than BCG and we hope that all patients who receive the vaccine wil I make a good immune response as opposed to only two thirds with BCG.

It is worth pointing out that this vaccine trial should have started in the U K. before that in the U.S. or Australia but has been held up by the Medical Control Agency for nearly 2 years for reasons which have not been of concern to the Food and Drugs Administration in the U S. or the other relevant authorities in Australia and New Zealand who have a reputation for being considerably more difficult to satisfy than most other medicine control agencies in the world.
 

Other vaccines

In addition to the gangliosides a number of other antigens have been identified over the last few years due to the sophisticated molecular approaches now available. A whole family of melanoma associated antigens called MAGE and MART as well as others are now available in peptide form for vaccination of patients with metastatic disease. Early studies show responses but the rates are in the same league as the cell based vaccines. The logical way forward for these vaccines is to combine a number of different antigens with a very good adjuvant and this is bound to occur in the next 2-3 years. Enhancing the immune response with dendritic cell pulsing whereby dendritic cells are grown up in the laboratory and matured and given back to the patients with antigens such as peptides or cells is already shown to induce a stronger immune response to some of these antigens. Other vaccines have involved the transfer of cytokine and other immune stimulants into cells which can either come from the patient themselves (autologous) or be prepared and optimised for their antigen expression from other people (allogeneic). The autologous approaches are unlikely to add significantly to the vaccination treatment of Stage III cancer as it is very difficult to get large numbers of cells to grow out of any individual patient. My own group has shown that allogeneic cells can induce just as good a response as most autologous and often stronger responses, presumably due to the foreignness of the cells acting as an extra immune stimulus or danger signal.

Other approaches which are being pursued include putting known antigens into virus vectors or cloning them as DNA and trying DNA based vaccines. One such approach in which the immunogen was foreign HLA induced good local responses and, in some cases, responses of metastases. If nothing else this study underlines the logic behind using allogeneic based vaccines.
 

Current vaccine trials in the United Kingdom for Stage III patients

Following the observation that high dose Interferon lead to a significant survival advantage in Stage III patients in the United States, a number of physicians feel that any trial should at least include this treatment even though it is relatively toxic and is very inconvenient for the years' administration that is required. We have commenced a study comparing the Morton vaccine against high dose Interferon for Stage III patients here at St. George's Hospital and hope that other Centres will join us throughout the United Kingdom in the near future. For those patients who wish to join a vaccine study that does not

have high dose Interferon then we have the 'Megavax' Study which is based on the new ganglioside vaccine, in which case patients will be offered the ganglioside vaccine or a placebo vaccine in a double blind fashion so neither the doctor not the patient will know who is on the active vaccine. This study is still awaiting final approval from the Medical Controls Agency but has the very real advantage it can be given and administered in virtually any Skin Department in the country with the minimum of training and back up and requires minimal documentation. The MCV vs. high dose Interferon Study requires considerably more infrastructure and expertise particularly with regards to the administration of high dose Interferon and therefore is more suitable for specialist units.
 

Stage IV disease

We have recently commenced recruiting patients who have metastatic disease which has been completely surgically removed into a trial with the Morton vaccine (MCV) vs. a placebo. which again is double blind and randomised. The Physician is completely at liberty to treat the patient however best they see fit so the patients are not denied any standard treatment and it al so gives the chance to assess the suggestion that patients who have had previous vaccination appear to respond better to chemotherapy and radiotherapy.
 

Other studies

A number of other studies are being planned and ethical permission sought at a number of Centres throughout the country These involve the use of the peptides mentioned above as well as trying dendritic cells to present antigens where peptides or cell based. A number of gene therapy based studies whereby a gene is inserted into the cell and then used as the vaccine have already been tried but at the current time, surprisingly, approaches do not appear to be any better than the more practical vaccination procedures mentioned above.
 

The near future

What is urgently required is a highly sensitive test for monitoring the response to melanoma vaccines allowing us to take therapeutic decisions based on these tests in advance of clinical escape by which time it may be too late to control a tumour without using other modalities. Over the last year it has certainly become very clear that patients who develop good cell mediated associated cytokine responses appear to do better than those that do not whatever type of vaccine they have received It is now possible to try and induce such responses using some of the newer adjuvant preparations starting to become available as well as using very low dose cytokines in addition to the vaccines. The fact that cancer vaccines are clearly the way forward for melanoma has been highlighted by 2 commercial developments, both of which have occurred only in the last few months. The first is the fact that Bristol Myers Squibb has bought a considerable interest in the company that makes the ganglioside vaccine and the second is that Shering Plough have bought the rights to a cell based vaccine which, in a randomised study, showed that it did no better than current chemotherapy agents. The importance of this latter observation was that, although it wasn't particularly effective, it was extremely non-toxic and given the choice between a highly toxic regime and a non-toxic vaccInation there is little doubt as to what most patient's physicians, not to mention their business managers, would chose. It is likely that this is just the beginning ofthe commercial development ofthis field.

 
Other cancer vaccines

The realisation that many antigens thought to be melanoma specific are shared by other solid tumours has reawakened interest in the idea of using vaccines against these more common tumours such as lung, breast, colo-rectal and prostate. There are now a number of studies which are showing promise in these common tumours. In colo-rectal cancer, a monoclonal antibody (Panorex) given to Duke's C patients post-resection has shown as good as survival data as ever claimed for 5 Fluorouracil which is the gold standard in spite of its unacceptable toxicity. A large study is now being conducted in many Centres in several countries by Glaxo-Wellcome who have taken over the rights to this antibody Although it is not a vaccine per se, some investigators have suggested that the protective effect may well be an antibody to the injected antibody otherwise known as a anti-idiotype response. Whether this is so still remains to be shown. Another anti-idiotype based vaccine where the monoclonal is given as an actual vaccine has been tried in Nottingham and this study, which showed some encouraging early data, did not live up to it's promise following a randomised study However, the study was conducted against the worst possible background with patients with advanced malignancy and a poor prognosis. Other vaccines are being developed for colo-rectal cancer, including cell based vaccines and virus based vaccines expressing known antigens such as the CEA antigen.
 

Prostate cancer.

 It has been known for some time that the immune response to the prostate has determined post prostatectomy is as good as indicator of prognosis as the famous Gleason score. Moreover, a randomised study using non-specific adjuvant based on BCG showed a survival advantage. At St. George's we have decided to focus on prostate cancer using 2 vaccines with which we are familiar in other studies. W e have shown that the non-specific immune stimulator known as SRL 172, which is a mycobacterium like BCG except that it is killed, can induce a favourable immune response even in patients with advanced prostate cancer. Moreover, we have also shown that there is a serious role for allogeneic cellular based vaccines (i.e.: cells raised from other tissues from other people and optimised for antigen expression etc) and we are planning to combine these 2 approaches in patients with rising PSA levels who have failed endocrine treatment. At least one other group is following a similar approach and another group are pulsing dendritic cells with peptides derived from PSMA, the prostate specific membrane antigen.

 
Breast cancer.

Vaccines targeting aberrant antigens in breast cancer are also under development with vaccines based on the abnormal mucin antigens (MUC-10 also being considered for other solid tumours in which they are expressed. Breast has it's own more specific targets such as erb-B2 as well as oestrogen receptors. A randomised study of one of these antigens in breast cancer has already shown a survival advantage in the patients receiving the vaccine, although it is too early to report.

 
Lung cancer:

There are a number of antigens shared between lung cancer and some of the other tumours, particularly the gangliosides and mucins. Studies using these antigens as single components have already commenced. In addition, non-specific immune stimulation with SRL 172 is looking promising in early studies.
 

Autologous vaccines for lymphoma and myeloma

Myeloma and lymphoma are unique in that they have their own private variable chain expressed as an antigen. The technology now exists to exploit this by 'PCR-ing' the particular tumour abnormality and making a DNA vaccine out of it. DNA vaccines are still in the early stages of development, but they have the potential to induce very strong mixed immune responses when injected into muscle cells. However, much more work is required with regards to promoters and other co-associated immune stimulants.

 
Gene therapy:

I have not discussed gene therapy up to now because it is clear that unless the immune response is enhanced and stimulated then current gene therapy approaches will be no more successful than current chemotherapy response. This is because it is going to be extremely difficult to target every cancer cell with a gene encoding some mechanism of killing the cancer cell and not the normal cell. One of these mechanisms which may well enter the Clinic in a wide variety of tumours which partly addressed this major drawback is a gene based on the enzyme from the herpes simplex virus known as HSV-tk which converts the relatively non-toxic antiviral Ganciclovir into a highly toxic phosphorylated form.

This can be introduce using viruses which will only target certain cell types and with specific promoters where by the TK gene of the herpes will only be turned on if it in the right cell. Some of these promoters may be tumour specific but at the very least if they are tissues specific then the ability to kill all cancer cells as well as normal cells would be achieving precisely the same ends as a Surgeon

Work on this approach showed that, even though only 3O-4O% of tumour cells in any one given individual animal could be infected with the gene therapy, the tumour often totally disappeared following administration of the Ganciclovir. This is very reproducible and a large component of this has been shown to be the immune response as the experiment does not work in animals who have a severe immune deficiency. This effect, where non infected cells are killed, is known as the bystander effect and if this can be contained entirely by the immune response then it is encouraging that we may be able to combine this form of gene therapy with immunotherapy/cancer vaccines (it is important to note that all cancer vaccine approaches will have to be given on a regular basis ~ i.e.: I -3 monthly as memory does not appear to be evoked by current cancer vaccine approaches).

It is likely that clinical trials involving this approach will become quite common in all the major solid tumours and the main limiting factor will be the supply of specific tissue or preferably tumour specific promoters.

Interestingly, most other forms of gene therapy that have been tried or are about to be tried in the Clinic also involve boosting the immune system and as such most of them are only fancy and expensive cancer vaccine approaches. However, true gene therapy approaches have been devised and clinical trials designed. One of the most elegant of these, in theory if not practice, is the design of an adenovirus which will kill cells that have abnormal suppresser genes and leave unaffected those with normal genes. The idea is that the gene would be taken into all tumour cells and only kill those with the abnormal gene and hence only cancer cells. This approach however by itself is not likely to be as effective as it's design would suggest as most solid tumours have diversified and developed several different pathways of abnormality and it is likely that cells will be selected with a different oncogene expression or a different mutant suppresser type in a similar manner to which solid tumour develop resistance to chemotherapy. Nevertheless, these approaches may compliment cancer vaccines in the near future
 

In conclusion :

Thanks to the pioneers who doggedly persisted with their attempts to stimulate the immune system in patients with melanoma, a renaissance in tumour immunology has taken place with the realisation that all solid tumours have some form of tumour associated antigen and, if not, a tumour specific antigen which can be exploited as a target for cancer vaccines. However the history of well conducted trials is littered with disappointments and for the first time we have the technology and the ability to overcome some of these variable factors. For instance, no appropriate adjuvant has been used in most studies when presenting the immune system with a tumour antigen and it is now clear we must invoke the right type of immune response. Results from gene therapy studies will probably be a lot slower in coming to the Clinic than the vaccine studies which have the advantages of being practical, of relatively low cost, and have very few side-effects especially compared with other forms of therapy I believe that gene therapy will slowly be used to augment the immune response to basic vaccines as discussed above with the gene therapy using viruses and vectors to actually kill cells without invoking an immune response remaining dependant upon developing good strategies to induce protective responses following the removal of any bulk disease by the gene therapy.