Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Cancer cell or component thereof
Reexamination Certificate
2001-09-07
2004-03-02
Mosher, Mary E. (Department: 1642)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Cancer cell or component thereof
C424S093210, C424S093300
Reexamination Certificate
active
06699483
ABSTRACT:
FIELD OF THE INVENTION
This invention is concerned with agents for the treatment of primary, metastatic and residual cancer in mammals (including humans) by inducing the immune system of the mammal or human afflicted with cancer to mount an attack against the tumour lesion. In particular, the invention pertains to the use of whole-cells, derivatives and portions thereof with or without vaccine adjuvants and/or other accessory factors. More particularly, this disclosure describes the use of particular combinations of whole-cells and derivatives and portions thereof that form the basis of treatment strategy.
BACKGROUND TO THE INVENTION
It is known in the field that cancerous cells contain numerous mutations, qualitative and quantitative, spatial and temporal, relative to their normal, non-cancerous counterparts and that at certain periods during tumour cells' growth and spread a proportion of these are capable of being recognised by the hosts' immune system as abnormal. This has led to numerous research efforts world-wide to develop immunotherapies that harness the power of the hosts' immune system and direct it to attack the cancerous cells, thereby eliminating such aberrant cells at least to a level that is not life-threatening (reviewed in Maraveyas, A. & Dalgleish, A. G. 1977
Active immunotherapy for solid tumours in vaccine design
in The Role of Cytokine Networks, Ed. Gregoriadis et al., Plenum Press, New York, pages 129-145; Morton, D. L. and Ravindranath, M. H. 1996
Current concepts concerning melanoma vaccines
in Tumor Immunology—Immunotherapy and Cancer Vaccines, ed. Dalgleish, A. G. and Browning, M., Cambridge University Press, pages 241-268. See also other papers in these publications for further detail).
Numerous approaches have been taken in the quest for cancer immunotherapies, and these can be classified under five categories:
Non-specific Immunotherapy
Efforts to stimulate the immune system non-specifically date back over a century to the pioneering work of William Coley (Coley, W. B., 1894 Treatment of inoperable malignant tumours with toxins of erisipelas and the Bacillus prodigosus. Trans. Am. Surg. Assoc. 12: 183). Although successful in a limited number of cases (e g. BCG for the treatment of urinary bladder cancer, IL-2 for the treatment of melanoma and renal cancer) it is widely acknowledged that non-specific immunomodulation is unlikely to prove sufficient to treat the majority of cancers. Whilst non-specific immune-stimulants may lead to a general enhanced state of immune responsiveness, they lack the targeting capability and also subtlety to deal with tumour lesions which have many mechanisms and plasticity to evade, resist and subvert immune-surveillance.
Antibodies and Monoclonal Antibodies
Passive immunotherapy in the form of antibodies, and particularly monoclonal antibodies, has been the subject of considerable research and development as anti-cancer agents. Originally hailed as the magic bullet because of their exquisite specificity, monoclonal antibodies have failed to live up to their expectation in the field of cancer immunotherapy for a number of reasons including immune responses to the antibodies themselves (thereby abrogating their activity) and inability of the antibody to access the lesion through the blood vessels. To date, three products have been registered as pharmaceuticals for human use, namely Panorex (Glaxo-Welicome), Rituxan (IDEC/Genentech/Hoffman la Roche) and Herceptin (Genentech/Hoffman la Roche) with over 50 other projects in the research and development pipeline. Antibodies may also be employed in active immunotherapy utilising anti-idiotype antibodies which appear to mimic (in an immunological sense) cancer antigens. Although elegant in concept, the utility of antibody-based approaches may ultimately prove limited by the phenomenon of ‘immunological escape’ where a subset of cancer cells in a mammalian or human subject mutates and loses the antigen recognised by the particular antibody and thereby can lead to the outgrowth of a population of cancer cells that are no longer treatable with that antibody.
Subunit Vaccines
Drawing on the experience in vaccines for infectious diseases and other fields, many researchers have sought to identify antigens that are exclusively or preferentially associated with cancer cells, namely tumour specific antigens (TSA) or tumour associated antigens (TAA), and to use such antigens or fractions thereof as the basis for specific active immunotherapy.
There are numerous ways to identify proteins or peptides derived therefrom which fall into the category of TAA or TSA. For example, it is possible to utilise differential display techniques whereby RNA expression is compared between tumour tissue and adjacent normal tissue to identify RNAs which are exclusively or preferentially expressed in the lesion. Sequencing of the RNA has identified several TAA and TSA which are expressed in that specific tissue at that specific time, but therein lies the potential deficiency of the approach in that identification of the TAA or TSA represents only a “snapshot” of the lesion at any given time which may not provide an adequate reflection of the antigenic profile in the lesion over time. Similarly a combination of cytotoxic T lymphocyte (CTL) cloning and expression-cloning of cDNA from tumour tissue has lead to identification of many TAA and TSA, particularly in melanoma. The approach suffers from the same inherent weakness as differential display techniques in that identification of only one TAA or TSA may not provide an appropriate representation of a clinically relevant antigenic profile.
Over fifty such subunit vaccine approaches are in development for the treatment of a wide range of cancers, although none has yet received marketing authorisation for use as a human pharmaceutical product. In a similar manner to that described for antibody-based approaches above, subunit vaccines may also be limited by the phenomenon of immunological escape.
Gene Therapy
The majority of gene therapy trials in human subjects have been in the area of cancer treatment, and of these a substantial proportion have been designed to trigger and/or amplify patients' immune responses. Of particular note in commercial development are Allovectin-7 and Leuvectin, being developed by Vical Inc for a range of human tumours, CN706 being developed by Calydon Inc for the treatment of prostate cancer, and StressGen Inc.'s stress protein gene therapy for melanoma and lung cancer. At the present time, it is too early to judge whether these and the many other ‘immuno-gene therapies’ in development by commercial and academic bodies will ultimately prove successful, but it is widely accepted that commercial utility of these approaches are likely to be more than a decade away.
Cell-based Vaccines
Tumours have the remarkable ability to counteract the immune system in a variety of ways including: downregulation of the expression of potential target proteins; mutation of potential target proteins; downregulation of surface expression of receptors and other proteins; downregulation of MHC class I and II expression thereby disallowing direct presentation of TAA or TSA peptides; downregulation of co-stimulatory molecules leading to incomplete stimulation of T-cells leading to anergy; shedding of selective, non representative membrane portions to act as decoy to the immune system; shedding of selective membrane portions to anergise the immune system; secretion of inhibitory molecules; induction of T-cell death; and many other ways. What is clear is that the immunological heterogeneity and plasticity of tumours in the body will have to be matched to a degree by immunotherapeutic strategies which similarly embody heterogeneity. The use of whole cancer cells, or crude derivatives thereof, as cancer immunotherapies can be viewed as analogous to the use of whole inactivated or attenuated viruses as vaccines against viral disease. The potential advantages are:
(a) whole cells contain a broad range of antigens, providing an antigeni
Dalgleish Angus George
Smith Peter Michael
Sutton Andrew Derek
Walker Anthony Ian
Heller Ehrman White & McAuliffe
Mosher Mary E.
Onyvax Limited
Yu Misook
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