Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Cancer cell or component thereof
Reexamination Certificate
1999-05-04
2002-10-01
Huff, Sheela (Department: 1642)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Cancer cell or component thereof
C424S184100, C424S193100, C424S278100, C424S520000, C424S573000, C435S325000
Reexamination Certificate
active
06458369
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to compositions comprising hapten-modified tumor cells and extracts and methods of treating cancer by administering a therapeutically effective amount of a composition comprising a tumor cell or tumor cell extract to a subject in need of such treatment. The invention also relates to an effective vaccination schedule useful for inducing an antitumor response in a patient suffering from cancer.
BACKGROUND OF THE INVENTION
It was theorized in the 1960's that tumor cells bear specific antigens (TSA) which are not present on normal cells and that the immune response to these antigens might enable an individual to reject a tumor. It was later suggested that the immune response to TSA could be increased by introducing new immunological determinants on cells. Mitchison,
Transplant. Proc.,
1970, 2, 92. Such a “helper determinant”, which can be a hapten, a protein, a viral coat antigen, a transplantation antigen, or a xenogenous cell antigen, could be introduced into a population of tumor cells. The cells would then be injected into an individual who would be expected to be tolerant to the growth of unmodified tumor cells. Clinically, the hope was that an immunologic reaction would occur against the helper determinants, as a consequence of which the reaction to the accompanying TSA is increased, and tumor cells which would otherwise be tolerated are destroyed. Mitchison, supra, also suggests several modes of action of the helper determinants including 1) that the unmodified cells are merely attenuated, in the sense that their growth rate is slowed down or their susceptibility to immunologic attack increased; 2) that helper determinants merely provide points of attack and so enable the modified cells to be killed by an immune response not directed against TSA; 3) that the helper determinants have an adjuvant action such as binding to an antibody or promoting localization of the cells in the right part of the body for immunization, in particular, in lymph nodes.
Fujiwara et al.,
J. Immunol.,
1984, 132, 1571 showed that certain haptenized tumor cells, i.e., tumor cells conjugated with the hapten trinitrophenyl (TNP), could induce systemic immunity against unmodified tumor cells in a murine system, provided that the mice were first sensitized to the hapten in the absence of hapten-specific suppressor T cells. Spleen cells from the treated mice completely and specifically prevented the growth of tumors in untreated recipient animals. Flood et al;,
J. Immunol.,
1987, 138, 3573 showed that mice immunized with a TNP-conjugated, ultraviolet light-induced “regressor” tumor were able to reject a TNP-conjugated “progressor” tumor that was otherwise non-immunologic. Moreover, these mice were subsequently resistant to challenge with unconjugated “progressor” tumor. In another experimental system, Fujiwara et al.,
J. Immunol.,
1984, 133, 510 demonstrated that mice sensitized to trinitrochlorobenzene (TNCB) after cyclophosphamide pretreatment could be cured of large (10 mm) tumors by in situ haptenization of tumor cells; subsequently, these animals were specifically resistant to challenge with unconjugated tumor cells.
The teachings of Fujiwara et al. differ from the present invention for several reasons including the following: A. The cells used in Fujiwara's composition are derived from induced transplantable murine tumors—not from spontaneous human tumors; B. Fujiwara's composition is used in immunoprophylaxis—the present invention uses immunotherapy; C. Fujiwara's composition is administered as a local therapy—the composition of the present invention is administered by systemic inoculation; and D. Fujiwara's composition did not result in tumor regression—the composition of the present invention results in regression and/or prolonged survival for at least a substantial portion of the patients treated.
The existence of T cells which cross-react with unmodified tissues has recently been demonstrated. Weltzien and coworkers have shown that class I MHC-restricted T c
6
ell clones generated from mice immunized with TNP-modified syngeneic lymphocytes respond to MHC-associated, TNP-modified “self” peptides. Ortmann, B.,: et al.,
J. Immunol.,
1992, 148, 1445. In addition, it has been established that immunization of mice with TNP-modified lymphocytes results in the development of splenic T cells that exhibit secondary proliferative and cytotoxic responses to TNP-modified cells in vitro. Shearer, G. M. Eur.
J. Immunol.,
1974, 4, 527. The potential of lymphocytes elicited by immunization with DNP- or TNP-modified autologous cells to respond to unmodified autologous cells is of considerable interest because it may be relevant to two clinical problems: 1) drug-induced autoimmune disease, and 2) cancer immunotherapy. In regard to the former, it has been suggested that ingested drugs act as haptens, which combine with normal tissue protein forming immunogenic complexes that are recognized by T cells. Tsutsui, H., et al.,
J. Immunol.,
1992, 149, 706. Subsequently, autoimmune disease, e.g., systemic lupus erythematosus, can develop and continue even after withdrawal of absence of the offending drug. This would imply the eventual generation of T lymphocytes that cross-react with unmodified tissues.
The common denominator of these experiments is sensitization with hapten in a milieu in which suppressor cells are not induced. Spleen cells from cyclophosphamide pretreated, TNCB-sensitized mice exhibited radioresistant “amplified helper function” i.e., they specifically augmented the in vitro generation of anti-TNP cytotoxicity. Moreover, once these amplified helpers had been activated by in vitro exposure to TNP-conjugated autologous lymphocytes, they were able to augment cytotoxicity to unrelated antigens as well, including tumor antigens (Fujiwara et al., 1984). Flood et. al., (1987), supra, showed that this amplified helper activity was mediated by T cells with the phenotype Lyt
−
1
+
, Lyt
−
2
−
, L3T4
+
, I
−
J
+
and suggests that these cells were contrasuppressor cells, a new class of immunoregulatory T cell.
Immunotherapy of patients with melanoma had shown that administration of cyclophosphamide, at high dose (1000 mg/M
2
) or low dose (300 mg/M
2
), three days before sensitization with the primary antigen keyhole limpet hemocyanin markedly augments the acquisition of delayed type hypersensitivity to that antigen (Berd et al.,
Cancer Res.,
1982, 42, 4862;
Cancer Res.,
1984, 44, 1275). Low dose cyclophosphamide pretreatment allows patients with metastatic melanoma to develop delayed type hypersensitivity to autologous melanoma cells in response to injection with autologous melanoma vaccine (Berd et al.,
Cancer Res.,
1986, 46, 2572;
Cancer Invest.,
1988, 6, 335). Cyclophosphamide administration results in reduction of peripheral blood lymphocyte non-specific T suppressor function (Berd et al.,
Cancer Res.,
1984, 44, 5439;
Cancer Res.,
1987, 47, 3317), possibly by depleting CD4+, CD45R+ suppressor inducer T cells (Berd et al.,
Cancer Res.,
1988, 48, 1671). The anti-tumor effects of this immunotherapy regimen appear to be limited by the excessively long interval between the initiation of vaccine administration and the development of delayed type hypersensitivity to the tumor cells (Berd et al.,
Proc. Amer. Assoc. Cancer Res.,
1988, 29, 408 (#1626)). Therefore, there remains a need to increase the therapeutic efficiency of such a vaccine to make it more immunogenic.
Most tumor immunologists now agree that infiltration of T lymphocytes, white cells responsible for tumor immunity, into the tumor mass is a prerequisite for tumor destruction by the immune system. Consequently, a good deal of attention has been focused on what has become known as “TIL” therapy, as pioneered by Dr. Stephen Rosenberg at NCI. Dr. Rosenberg and others have extracted from human cancer metastases the few T lymphocytes that are naturally present and greatly expanded their numbers
Darby & Darby
Huff Sheela
Hunt Jennifer
Thomas Jefferson University
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