Caring for one of our own.

Schwartz Center Rounds are monthly multidisciplinary meetings where caregivers reflect on important psychosocial issues that they, along with patients and their families, face and gain insight and support from fellow staff members, with the goal of advancing compassionate health care, supporting caregivers, and fostering the connection between a clinician and his or her patients. This Schwartz Round focused on boundaries and the particular privileges and pressures of caring for a member of the staff. The article explores the tension between professional courtesy and empathic engagement.

Adoptive transfer of autologous natural killer cells leads to high levels of circulating natural killer cells but does not mediate tumor regression.

Purpose: Adoptive transfer of tumor-infiltrating lymphocytes (TIL) can mediate regression of metastatic melanoma. However, many patients with cancer are ineligible for such treatment because their TIL do not expand sufficiently or because their tumors have lost expression of antigens and/or MHC molecules. Natural killer (NK) cells are large granular lymphocytes that lyse tumor cells in a non-MHC-restricted manner.

A TCR targeting the HLA-A*0201-restricted epitope of MAGE-A3 recognizes multiple epitopes of the MAGE-A antigen superfamily in several types of cancer.

Adoptive immunotherapy using TCR-engineered PBLs against melanocyte differentiation Ags mediates objective tumor regression but is associated with on-target toxicity. To avoid toxicity to normal tissues, we targeted cancer testis Ag (CTA) MAGE-A3, which is widely expressed in a range of epithelial malignancies but is not expressed in most normal tissues. To generate high-avidity TCRs against MAGE-A3, we employed a transgenic mouse model that expresses the human HLA-A*0201 molecule.

Characterization of genetically modified T-cell receptors that recognize the CEA:691-699 peptide in the context of HLA-A2.1 on human colorectal cancer cells.

Purpose: Carcinoembryonic antigen (CEA) is a tumor-associated protein expressed on a variety of adenocarcinomas. To develop an immunotherapy for patients with cancers that overexpress CEA, we isolated and genetically modified a T-cell receptors (TCRs) that specifically bound a CEA peptide on human cancer cells.

Experimental Design: HLA-A2.

Extrathymic generation of tumor-specific T cells from genetically engineered human hematopoietic stem cells via Notch signaling.

Adoptive cell transfer (ACT) of tumor-reactive lymphocytes has been shown to be an effective treatment for cancer patients. Studies in murine models of ACT indicated that antitumor efficacy of adoptively transferred T cells is dependent on the differentiation status of the cells, with lymphocyte differentiation inversely correlated with in vivo antitumor effectiveness. T-cell in vitro development technologies provide a new opportunity to generate naive T cells for the purpose of ACT.

Immunization of patients with the hTERT:540-548 peptide induces peptide-reactive T lymphocytes that do not recognize tumors endogenously expressing telomerase.

Purpose: Telomerase is an attractive target antigen for cancer immunotherapies because it is expressed in >85% of human tumors but is rarely found in normal tissues. A HLA-A*0201-restricted T-cell epitope was previously identified within telomerase reverse transcriptase hTERT:540-548. This peptide was reported to induce CTL that recognized tumor cells and transfectants that endogenously expressed telomerase.

Induction of CD4+ Th1 lymphocytes that recognize known and novel class II MHC restricted epitopes from the melanoma antigen gp100 by stimulation with recombinant protein.

CD4+ T helper cells may play a critical role in the induction and maintenance of a therapeutic immune response to cancer. To evaluate the efficacy with which a recombinant tumor-associated protein can induce antigen-reactive CD4+ T cells, we stimulated peripheral blood lymphocytes from patients with melanoma in vitro with the purified melanoma antigen gp100 produced in Escherichia coli. In preliminary experiments, we observed that peripheral blood mononuclear cells could process and present known HLA-DRbeta1*0401 and HLA-DRbeta1*0701 restricted epitopes to gp100-reactive CD4+ T cell lines after being loaded exogenously with protein.

Stimulation of tumor-reactive T lymphocytes using mixtures of synthetic peptides derived from tumor-associated antigens with diverse MHC binding affinities.

The use of reverse immunology may be necessary to identify new tumor-associated antigens, particularly for cancers, against which tumor-reactive T cell populations have been difficult to establish. One approach has been to screen peptides derived from a candidate antigen with high major histocompatibility complex (MHC) binding affinities for the induction of tumor-reactive T lymphocytes in vitro. However, many candidate antigens that are overexpressed in tumors are nonmutated self-proteins, and unlike foreign or mutated proteins, immunodominant epitopes may not be expressed at high density on the surface of tumor cells.

Hybrids of dendritic cells and tumor cells generated by electrofusion simultaneously present immunodominant epitopes from multiple human tumor-associated antigens in the context of MHC class I and class II molecules.

Hybrid cells generated by fusing dendritic cells with tumor cells (DC-TC) are currently being evaluated as cancer vaccines in preclinical models and human immunization trials. In this study, we evaluated the production of human DC-TC hybrids using an electrofusion protocol previously defined for murine cells. Human DCs were electrically fused with allogeneic melanoma cells (888mel) and were subsequently analyzed for coexpression of unique DC and TC markers using FACS and fluorescence microscopy.

Identification of BING-4 cancer antigen translated from an alternative open reading frame of a gene in the extended MHC class II region using lymphocytes from a patient with a durable complete regression following immunotherapy.

Multiple human cancer Ags have been identified, although little is known concerning which would be most effectively used in cancer immunotherapy. To gain insight into the selection of appropriate Ags, the immunologic reactivity of a patient who had a durable complete regression of melanoma metastases was measured. PBMCs were directly cloned using the monoclonal anti-CD3 Ab OKT3 and IL-2 without any bias introduced by previous culture.

Identification of a New Shared HLA-A2.1 Restricted Epitope From the Melanoma Antigen Tyrosinase.

SUMMARY: Tyrosinase has many advantages as a target antigen for the immunotherapy of patients with melanoma because it is expressed in nearly all melanoma specimens with a high degree of cellular homogeneity, and its distribution in normal tissues is limited to melanocytes. To broaden our ability to direct cellular immune responses against this protein, we pursued an investigation to identify new shared human leukocyte antigen (HLA)-A2.1 restricted epitopes from tyrosinase.