Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector
Reexamination Certificate
1999-10-05
2002-06-18
Huff, Sheela (Department: 1642)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
C424S278100, C424S193100, C424S195110, C424S198100, C424S277100
Reexamination Certificate
active
06406699
ABSTRACT:
BACKGROUND OF THE INVENTION
A. T
HE
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MMUNE
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YSTEM AND
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ANCER
The mammalian immune system uses two general adaptive mechanisms to protect the body against environmental pathogens. One is the non-specific (or innate) inflammatory response. The other is the specific or acquired (or adaptive) immune response. Innate responses are fundamentally the same for each injury. In contrast, acquired responses are custom tailored to the pathogen.
The immune system recognizes and responds to structural differences between self and non-self proteins. Proteins that the immune system recognizes as non-self are called “antigens”. Pathogens express large numbers of highly complex antigens. Acquired immunity has specific “memory” for antigenic structures, and repeated exposure to the same antigen increases the response, which increases the level of induced protection against that particular pathogen.
Acquired immunity is mediated by specialized immune cells called B and T lymphocytes. B lymphocytes produce and mediate their functions through the actions of antibodies. B lymphocyte dependent immune responses are referred to as “humoral immunity” because antibodies are detected in body fluids. T lymphocyte dependent immune responses are referred to as “cell mediated immunity” because effector activities are mediated directly by the local actions of effector T lymphocytes. The local actions of effector T lymphocytes are amplified through synergistic interactions between T lymphocytes and secondary effector cells, such as activated macrophages. The result is that the pathogen is killed and thereby prevented from causing disease.
Cancer immunity is mediated exclusively by T lymphocytes, which means that it involves acquired cell mediated immunity and does not involve B lymphocytes or antibodies. An activated acquired immune response kills cancer cells and rejects the cancer.
Medical interventions often make use of the fact that acquired immune responses can be artificially manipulated. Exposing individuals to a weakened pathogen induces acquired immunity without causing disease and protects the individual against later exposure to the same pathogen. The general process of artificially inducing protective immune responses is called vaccination. Protective immunity to some pathogenic agents can be transferred from one individual to another using T lymphocytes. Although cancer immunity can be transferred between individuals using T lymphocytes, currently there are no accepted medical interventions that employ T lymphocyte transfer between individuals.
Vaccines are mainly useful for disease prevention. Vaccination has been used to induce protection against a wide variety of environmental pathogens, particularly viruses. The dramatic success that has been achieved with vaccines has led to a search for therapeutic applications. The search for a therapeutic AIDS vaccine is one well-known example. Unfortunately, manipulating the immune system to treat pre-existing disease has proven much more difficult than manipulating the immune system for protection. The only well-documented success against human disease has been achieved in rabies. Multiple vaccinations can prevent rabies from developing after exposure to the virus. The same general rationale has been applied to cancer treatment. The thought has been that, since, unlike viruses, cancers are relatively slow growing, it could be possible to use vaccines to slow or prevent further growth or spread. However, only very limited success has been achieved with cancer vaccines.
It is not intuitive that malignancies would be susceptible to immune manipulation. Malignant cells are genetically altered normal cells, not foreign pathogens. The immune system must be able to recognize malignant cells as non-self, and it must be possible to manipulate the immune system to reject cancer cells that may have spread to remote body sites. Although malignant cells are not actually foreign pathogens, there is widespread agreement that malignant cells can be recognized as non-self Cancer antigens are generated from the genetic changes that cancer cells go through during malignant transformation and progression. See Srivastava, Do Human Cancers Express Shared Protective Antigens? Or the Necessity of Remembrance of Things Past, Semnin. Immunol. 8:295-302 (1996). However, the extent to which the immune system of patients with progressing cancers can be manipulated is extremely controversial. See Ellem et al., The Labyrinthine Ways of Cancer Immunotherapy—T Cell, Tumor Cell Encounter: “How Do I Lose The? Let Me Count The Ways,” Adv. Canc. Res. 75:203-249 (1998). This is mainly due to the fact that, like attempts to use the immune system to treat infectious disease, attempts to manipulate the immune system for the therapeutic benefit of cancer patients have been largely unsuccessful. Controversy about the potential susceptibility of human cancer to immune manipulation also arises from the fact that it is widely believed that human malignancies are weakly immunogenic. Consequently, there have been very few systematic attempts to determine the relative immunogenicity of human cancers.
How do researchers determine whether a substance is antigenic or that an acquired immune response has been induced in an individual that has been exposed to an antigen? For humoral immunity, there is a myriad of in vitro assays for measuring an increase in serum antibody levels. It is infinitely more difficult, however, to determine that a cell mediated immune response has been induced. Over the years, in vivo protection assays have proven to be the most reliable indicators when the antigen is a pathogen. Protection assays work well when the antigen in question causes disease and when the studies are being performed in experimental models. An individual is vaccinated with the antigen in question, then challenged with increasing quantities of the pathogenic agent. Thus, in the case of cancer, mice are exposed to a cancer vaccine, then injected later with live cancer cells. If the cancer cells fail to grow, then the animal is immune and one can infer that an immune response was induced. That approach also can be used to quantitate and determine the specificity of the response.
Protection experiments cannot be used to measure anti-cancer immune responses in humans because it would be unethical to inject patients with cancer-causing cells. Since cancer antigens remain to be defined and cell mediated immune responses against cancer involve a complex, poorly understood interplay between several T lymphocyte subpopulations, there is no simple, reliable way to quantitate such responses in vitro. Instead, delayed type hypersensitivity (“DTW”) skin testing assays were developed long ago as an alternative in vivo assay for cell mediated immunity. The DTHl reaction takes advantage of the fact that an immune animal or human develops an acquired cellular immune reaction that is characterized by redness and swelling that occurs within 24 to 48 hours following injection of antigen into the site.
Although there are in vitro assays that may be able to be routinely used in the future, the DTH reaction is the only method that has been used so far to measure immune responses against a cancer antigens in humans. See Berd et al., Treatment of Metastic Melanoma with Autologous Tumor Cell Vaccine: Clinical and Immunologic Results in 64 Patients, J. Clin. Oncol. 8:1858-1865 (1990); Hoover & Hanna, Active Immunotherapy in Colorectal Cancer, Semin. Surg. Oncol. 5:436-440 (1989); Lehner et al., Postoperative Active Specific Immunization in Curatively Resected Colorectal Cancer Patients with a Virus-Modified Autologous Tumor Cell Vaccine, Cancer Immunol. Immunother. 32:173-178 (1990). The reasons for this are fourfold. First, although malignant cells are immunogenic, no specific human cancer antigen has yet been identified, characterized, and purified from such cells. Second, DTH responses, like tumor immunity, are mediated locally by a combination of activated Th1 lymphocytes and non-cytotoxic, Th1-like CD8 T
Harris Alana M.
Huff Sheela
Sonnenschein Nath & Rosenthal
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