Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Animal cell – per se – expressing immunoglobulin – antibody – or...
Reexamination Certificate
1999-10-20
2002-06-25
Ketter, James (Department: 1632)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Animal cell, per se, expressing immunoglobulin, antibody, or...
C435S320100, C435S325000, C435S326000, C435S328000, C435S332000, C435S343000, C435S344000, C435S372000, C435S372200, C435S372300, C536S023100, C536S023400
Reexamination Certificate
active
06410319
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Technical Field
This invention relates to the field of genetically engineered, redirected T cells and to the field of cellular immunotherapy of malignancies such as Non-Hodgkin's lymphoma and lymphocytic leukemia.
2. Description of Related Art
Over 30,000 new cases of Non-Hodgkin's lymphoma are diagnosed each year in the United States alone. (Shipp et al., Cancer:
Principles and Practice of Oncology,
Lippincott-Raven Publishers, Philadelphia, 1997, p2165). While current therapies have produced significant complete response rates, a large percentage of patients remain at significant risk for disease relapse (Glass et al.,
Cancer
80:2311, 1997). Immune-based strategies for targeting minimal residual disease are under development and may provide additional modalities for consolidating standard chemotherapy and radiotherapy regimens. The approach of treating lymphoma with adoptive T cell therapy is predicated on the assumptions that tumor-reactive T cells can be isolated from individuals with lymphoma and expanded in vitro, and that infusion of the expanded effector population into the patient will mediate an antitumor effect without significant toxicity. Adoptively transferred donor-derived Epstein-Barr virus (EBV)-specific T cells can eliminate transformed B cells as demonstrated in the setting of post-transplant EBV-associated lymphoproliferative disease (Heslop et al.,
Immunol. Rev.
157:217, 1997). The clinical application of cellular immunotherapy for lymphoma using autologous T cells is currently limited by the paucity of molecularly-defined lymphoma target antigens for T cell recognition and the challenges of reliably isolating and expanding tumor-antigen specific T cell responses from cancer patients.
In order to overcome these obstacles, we and others are evaluating chimeric antigen receptor constructs consisting of a monoclonal antibody single chain Fv (scFv) linked to the intracellular signaling domain of CD3 zeta or Fc&ggr;RIII for the purpose of re-directing T cell specificity. This strategy allows for the targeting of tumor cells based on the binding of the scFv portion of the receptor to monoclonal antibody-defined cell-surface epitopes. The capacity of these receptors when expressed in T cells to trigger cytokine production and cytolysis in vitro is now well established in both murine and human T cells. See Gross et al.,
FASEB J.
6:3370, 1992; Eshhar et al.,
PNAS USA,
90:720, 1993; Stancovski et al.,
J. Immunol.,
151:6577, 1993; Moritz et al.,
PNAS USA
91:4318, 1994; Hwu et al.,
Cancer Res.,
55:3369, 1995; Weitjens et al.,
J. Immunol.
157:836, 1996. Animal model systems demonstrate the capacity of murine T cell transfectants to eradicate tumor in vivo, suggesting that these gene-modified cells retain appropriate homing and recycling mechanisms (Hekele et al., Int.
J. Cancer
68:232, 1996). This system is not dependent on pre-existing antitumor immunity since the generation of tumor-reactive T cells for therapy can be accomplished by the genetic modification of polyclonal T cells present in peripheral blood. Moreover, target epitope recognition by scFv is not HLA-restricted, thereby permitting the use of receptor constructs in populations of lymphoma patients irrespective of HLA differences.
A critical aspect of this chimeric receptor strategy is the selection of target epitopes that are specifically or selectively expressed on tumor, are present on all tumor cells, and are membrane epitopes not prone to shed or modulate from the cell surface. Nearly 80% of Non-Hodgkin's lymphoma are B cell in origin and are defined in part by the cell surface expression of the CD20 molecule. This 33-37 KD protein is uniformly expressed on normal B cells and malignant B cells at a density greater than 12,000 molecules per cell (Vervoordeldonk et al.,
Cancer
73:1006, 1994). CD20 does not modulate or shed from the cell surface and has structural features consistent with that of an ion channel (Press et al.,
Blood
83:1390, 1994; Bubien et al.,
J. Cell Biol.
121:1121, 1993). The United States Food and Drug Administration (FDA) has approved a chimeric CD20-specific monoclonal antibody (rituximab) for lymphoma therapy. Initial clinical experience with CD20-targeted immunotherapy suggests that malignant B cells may have a limited capacity to down regulate CD20 expression. These attributes make CD20 an attractive target for genetically engineered, redirected T cells.
CD8
+
cytolytic T cells (CTL) are immunologic effector cells that have the capacity to specifically recognize and directly lyse target cells (Henckart,
Semin. Immunol.
9:85, 1997). Re-infusion of ex vivo expanded tumor-specific CD8
+
CTL clones can mediate tumor eradication as demonstrated in animal model systems (Greenberg,
Adv. Immunol.
49:281,1991). A growing number of genes encoding proteins expressed by human tumors that elicit T cell responses have been identified by expression cloning technologies. (Robbins et al.,
Current Opin. Immunol.
8:628, 1996; De Plaen et al.,
Methods
12:125, 1997). The feasibility of isolating T cells from cancer patients with specificity for these molecularly defined tumor antigens is currently being evaluated but remains a significant challenge to the clinical application of adoptive T cell therapy for malignant disease (Yee et al.,
J. Immunol.
157:4079, 1996).
Endowing T cells with tumor specificity by gene transfer of cDNA constructs encoding engineered antigen receptors is an alternate strategy for generating tumor-reactive CTL for therapy. (Weiss et al.,
Semin. Immunol.
3:313, 1991; Gross et al., supra; Hedrick et al.,
Int. Rev. Immunol.
10:279, 1993). These cell-surface chimeric molecules are distinguished by their ability to both bind antigen and transduce activation signals via immunoreceptor tyrosine-based activation motifs (ITAM's) present in their cytoplasmic tails. Receptor constructs utilizing an antigen-binding moiety generated from single chain antibodies (scFv) afford the additional advantage of being “universal” in that they bind native antigen on the target cell surface in an HLA class I independent fashion. Several laboratories have reported on scFv constructs fused to sequences coding for the intracellular portion of the CD3 complex's zeta chain (&zgr;), the Fc receptor gamma chain, and sky tyrosine kinase (Eshhar et al., supra; Fitzer-Attas et al.,
J. Immunol.
160:145, 1998). Re-directed T cell effector mechanisms including tumor recognition and lysis by CTL have been documented in several murine and human antigen-scFv:&zgr; systems (Eshhar,
Cancer Immunol. Immunother.
45:131, 1997; Altenschmidt et al.,
J. Mol. Med.
75:259, 1997; Brocker et al.,
Adv. Immunol.
68:257, 1998.
Clinical cellular immunotherapy trials have utilized gene-modified T cells for gene marking purposes, the expression of suicide genes permitting in vivo ablation of transfected cells, the expression of genes designed to protect T cells from HIV infection, and the expression of chimeric antigen receptors (Rosenberg et al.,
Human Gene Therapy
8:2301, 1997). A growing number of applications of T cell gene therapy for manipulating T cell survival, trafficking, and effector functions are under development for clinical application. To date, retroviral vectors remain the preeminent modality for gene transfer into primary human T cells. These vectors provide for relatively high transduction efficiencies and stable chromosomal integration but place constraints on the sequence and amount of cDNA which can be packaged and are difficult, time consuming, and expensive to produce as clinical grade material. A gene transfer system that provides a high degree of flexibility with respect to the configuration and sequence of cDNA constructs, that can be rapidly modified, and that is non-infectious and inexpensive to produce as a clinical reagent, may provide a viable alternative to retroviral systems.
Plasmid DNA represents a highly versatile platform for constructing expression cassettes that are active in
Jensen Michael C.
Raubitschek Andrew
Wu Anna
City of Hope
Ketter James
Li Q. Janice
LandOfFree
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