Details of a Researcher - Kawakami, Yutaka

Papers - Kawakami, Yutaka

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In situ canver vaccination using a mutant HSV-1 for the treatment of metastatic brain tumor

Toda Masahiro, Iizuka Yukihiko, Yazaki Takahito, Kawase Takeshi, Uyemura Keiichi, Kawakami Yutaka

Neuro-Oncology 1 ( suppl ) S105-S105 1999.10

Research paper (scientific journal), Joint Work

造血器腫瘍における腫瘍抗原と免疫療法

Matsushita Maiko, Ikeda Hideyuki, Kawakami Yutaka

現代医療 31 ( 5 ) 1155-1160 1999.05

Research paper (scientific journal), Joint Work

転移性腫瘍に対する免疫療法・免疫遺伝子治療の現状と展望

Kitagawa Yukou, Kawakami Yutaka, Kitajima Masaki

臨床外科 54 ( 2 ) 203-208 1999.02

Research paper (scientific journal), Joint Work

Key points for development of immunotherapy for cancer using T cell defined tumor antigens

Kawakami Y.

Biotherapy 13 ( 5 ) 429 - 433 1999

ISSN 0914-2223

PRAME protein expressed in leukemia cells as a target molecule for immunotherapy.

池田英之，松下麻衣子，河上裕

Rinsho Ketsueki 40 ( 6 ) 484-486 1999

Research paper (scientific journal), Joint Work

Identification of human melanoma antigens recognized by tumor infiltrating T lymphocytes and their use for immunotherapy

Kawakami Y.

Gann Monographs on Cancer Research 48 179 - 189 1999

ISSN 0072-0151

Adoptive transfer of cultured tumor infiltrating T-lymphocytes (TIL) with interleukin 2 (IL2) resulted in tumor regression in melanoma patients, indicating the important role of T-cells in mediating in vivo melanoma regression. TIL secrete cytokines and lyse tumor cells in vitro by recognizing autologous melanoma. Using cDNA expression cloning methods with these TIL, cDNAs encoding melanoma antigens including 5 melanosomal proteins (MART-1, gp100, tyrosinase, TRP1, and TRP2), p15 and β-catenin, were identified. Non-mutated and mutated T cell epitopes have also been identified. A variety of mechanisms to generate these T cell epitopes on melanoma has been identified including peptides derived from regular open reading frames (ORFs), an alternative ORF, introns, or sequences with a mutation. Some melanoma epitopes had relatively low major histocompatibility complex (MHC) binding affinities, suggesting that these were subdominant self epitopes. Several MART-1 and gp100 epitopes were recognized by TIL from many patients, suggesting that these were immunodominant common epitopes. By in vitro stimulation with these identified epitopes, melanoma reactive cytotoxic T lymphocytes (CTL) could be efficiently induced from peripheral blood lymphocytes (PBL) or TIL of melanoma patients. Since adoptive transfer of the TIL reacting to these melanoma antigens into autologous patients with IL2 resulted in tumor regression, these peptides may function as tumor rejection antigens. Tumor regression correlated with vitiligo development after IL2 based immunotherapies in melanoma indicating that these epitopes may also be present on the surface of melanocytes in vivo and that autoreactive T-cells may be involved in the tumor regression. A variety of Phase I clinical trials including immunization with the MART-1 and gp100 peptides, or recombinant viruses containing the MART-1 or gp100 gene, with or without administration of cytokines such as IL2, granulocyte macrophagecolony stimulating factor (GM-CSF), IL12, is being conducted in the Surgery Branch of the National Cancer Institute (NCI), and tumor regression has been observed in some patients.

Identification of new melanoma epitopes on melanosomal proteins recognized by tumor infiltrating T lymphocytes restricted by HLA-A1, -A2, and -A3 alleles

Kawakami Yutaka, Robbins Paul F., Wang Xiang, Tupesis Janis P., Parkhurst Maria R., Kang Xiaoqiang, Sakaguchi Kazuyasu, Appella Ettore, Rosenberg Steven A.

Journal of Immunology 161 ( 12 ) 6985 - 6992 1998.12

ISSN 0022-1767

To isolate melanoma Ags recognized by T cells, cDNA libraries made from melanoma cell lines were screened with four CTLs derived from tumor infiltrating lymphocytes (TIL) that were able to recognize melanoma cells in a HLA-A1, -A2, or -A3 restricted manner. Although cDNAs encoding the previously identified melanoma Ags, tyrosinase and gp100, were isolated, these TIL were found to recognize previously unidentified peptides. An HLA- A1-restricted CTL, TIL1388, was found to recognize a tyrosinase peptide (SSDYVIPIGTY), and an HLA-A3-restricted CTL, TIL1351, recognized a gp100 peptide (LIYRRRLMK). CTL clones isolated from the HLA-A2-restricted TIL1383 recognized a gp100 peptide (RLMKQDFSV). HLA-A2-restricted CTL, TIL1200, recognized a gp100 peptide (RLPRIFCSC). Replacement of either cysteine residue with α-amino butyric acid in the gp100 peptide, RLPRIFCSC, enhanced CTL recognition, suggesting that the peptide epitope naturally presented on the tumor cell surface may contain reduced cysteine residues. Oxidation of these cysteines might have occurred during the course of the synthesis or pulsing of the peptide in culture. These modifications may have important implications for the development of efficient peptide-based vaccines. These newly identified peptide epitopes can extend the ability to perform immunotherapy using synthetic peptides to a broader population of patients, especially those expressing HLA-A1 or HLA-A3 for whom only a few melanoma epitopes have previously been identified.

Identification of a shared HLA-A*0201-restricted T-cell epitope from the melanoma antigen tyrosinase-related protein 2 (TRP2)

Parkhurst Maria R., Fitzgerald Ellen B., Southwood Scott, Sette Alessandro, Rosenberg Steven A., Kawakami Yutaka

Cancer Research 58 ( 21 ) 4895 - 4901 1998.11

ISSN 0008-5472

Tyrosinase-related protein 2 (TRP2) is a melanosomal enzyme expressed in most mammalian melanocytes and melanomas. This protein has been identified as a melanoma antigen recognized by tumor reactive CTLs derived from tumor infiltrating lymphocytes in the context of HLA-A31 and HLA-A33. The frequencies of these HLA-A alleles among melanoma patients in the United States is low (~6% for HLA-A31 and ~2% for HLA-A33) compared with that of HLA-A*0201 (~46%). Therefore, to extend significantly the use of TRP2- based immunotherapies for the treatment of patients with melanoma, we searched for new HLA-A*0201-restricted epitopes from this protein by screening TRP2-derived peptides for the induction of melanoma-reactive CTL. Fifty-one peptides were selected from TRP2 based on a permissive HLA-A*0201 binding motif, and the 21 peptides with the highest experimentally determined binding affinities were used to stimulate peripheral blood lymphocytes from HLA-A*0201⁺ melanoma patients in vitro. One peptide, TRP2(180188) (SVYDFFVWL), induced CTLs from three of four patients that specifically recognized peptide-pulsed T2 cells, COS-7 cells expressing HLA-A*0201 and TRP2, and HLA-A2⁺ TRP2⁺ melanomas. TRP2(180188) is identical to a previously identified TRP2 epitope recognized by murine melanoma-reactive CTLs in the context of H-2K^b. These results suggest that TRP2 may be useful for the development of murine tumor immunotherapy models and for the treatment of melanoma patients who are diverse in HLA expression.

Immunotherapy using T cell defined tumor antigens for melanoma

Kawakami Yutaka

Microbiology and Immunology 42 ( 12 ) 803 - 813 1998

ISSN 0385-5600

Immunotherapy using human melanoma epitopes recognized by T cells

Kawakami Y.

Biotherapy 12 ( 5 ) 542 - 548 1998

ISSN 0914-2223

Tumor reactive T cells can be induced from peripheral blood or tumor infiltrating lymphocytes of patients with melanoma. Based on the analysis of the previous immunotherapies, T cells appeared to be involved in vivo tumor regression. Genes encoding human melanoma antigens and their epitope peptides recognized by T cells, have been identified using cDNA expression cloning techniques. Mechanisms for generation of T cell epitopes on growing melanoma cells have been identified. A variety of Phase I clinical studies using MART- 1 and gp100 antigens are being performed in the Surgery Branch, National Cancer Institute, NIH, and some patients have responded to these immunotherapy protocols.

Identification of the genes encoding cancer antigens

Rosenberg S. A., Kawakami Y., Robbins P. F., Wang R. F.

Advances in Cancer Research 70 145 - 177 1998

ISSN 0065-230X

Development of new immunotherapies using melanoma antigens recognized by T cells

Kawakami Y.

Biotherapy 12 ( 9 ) 1187 - 1194 1998

ISSN 0914-2223

Melanoma is a relatively immunogenic cancer and a good model to evaluate the possibilities of immunotherapies. Recent progress of molecular biology and immunology has allowed us to understand immune responses to human cancer at the molecular level. Although antigens for CD4⁺ T cells have not well been identified, various melanoma antigens recognized by CD8⁺ T cells have been identified, including tissue specific proteins (melanosomal proteins), proteins expressed in testis and a variety of cancers (Cancer-Testis antigens) and tumor specific mutated proteins. The immunological features of these antigens have been characterized for development of new immunotherapies. Based on these findings, antigen specific immunotherapies have been developed. Some of the phase I clinical trials with the identified melanoma antigens demonstrated anti-tumor effects. Immunization with the modified gp100 epitope that had high MHC binding affinity, in conjunction with incomplete freund adjuvant and high-dose IL-2, resulted in a 42 % response rate (CR+PR). Immunization with dendritic cells pulsed with tumor lysates or epitope peptides resulted in a 31 % response rate in metastatic melanoma. These immunotherapies need to be improved through modifications and better understanding of tumor escape mechanisms.

The use of melanosomal proteins in the immunotherapy of melanoma

Kawakami Yutaka, Robbins Paul F., Wang Rong Fu, Parkhurst Maria, Kang Xiaoqiang, Rosenberg Steven A.

Journal of Immunotherapy 21 ( 4 ) 237 - 246 1998

ISSN 1053-8550

Clinical observations in the interleukin (IL) 2-based immunotherapies suggest that T cells play a central role in the rejection of melanoma. Using cDNA expression cloning, we have isolated genes encoding melanoma antigens recognized by tumor-infiltrating T lymphocytes. These antigens are categorized as (a) melanocyte-specific melanosomal proteins (MART-1/melan A, gp100, tyrosinase, TRP-1, and TRP-2), (b) tumor-specific mutated proteins (β-catenin), and (c) others (p15). A variety of mechanisms has been identified for the generation of T cell epitopes on tumor cells. Some of the HLA-A2 binding epitopes from the melanosomal antigens appear to be subdominant self-determinants with relatively low major histocompatibility complex binding affinity. The effectiveness of adoptive transfer into patients of cytotoxic T lymphocytes recognizing the melanosomal antigens, the significant correlation between vitiligo development and clinical response in patients receiving IL-2-based immunotherapies, and the sporadic tumor regressions observed in some patients following immunization with the MART-1 or gp100 peptides in incomplete Freund's adjuvant or recombinant viruses expressing the MART-1 antigen suggest that these epitopes may represent tumor rejection antigens. Phase I immunization trials using peptides or recombinant viruses containing genes encoding the melanosomal antigens MART- 1 or gp100, with or without co-administration of cytokines such as IL-2, IL-12, or granulocyte-macrophage colony-stimulating factor, are being conducted in the Surgery Branch of the National Cancer Institute. These studies may demonstrate the feasibility of using melanosomal proteins for the immunotherapy of patients with melanoma.

Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma

Rosenberg Steven A., Yang James C., Schwartzentruber Douglas J., Hwu Patrick, Marincola Francesco M., Topalian Suzanne L., Restifo Nicholas P., Dudley Mark E., Schwarz Susan L., Spiess Paul J., Wunderlich John R., Parkhurst Maria R., Kawakami Yutaka, Seipp Claudia A., Einhorn Jan H., White Donald E.

Nature Medicine 4 ( 3 ) 321 - 327 1998

ISSN 1078-8956

The cloning of the genes encoding cancer antigens has opened new possibilities for the treatment of patients with cancer. In this study, immunodominant peptides from the gp100 melanoma-associated antigen were identified, and a synthetic peptide, designed to increase binding to HLA-A2 molecules, was used as a cancer vaccine to treat patients with metastatic melanoma. On the basis of immunologic assays, 91% of patients could be successfully immunized with this synthetic peptide, and 13 of 31 patients (42%) receiving the peptide vaccine plus IL-2 had objective cancer responses, and four additional patients had mixed or minor responses. Synthetic peptide vaccines based on the genes encoding cancer antigens hold promise for the development of novel cancer immunotherapies.

Access to Document (DOI)

T細胞が認識するヒトメラノーマ抗原の単離同定と免疫遺伝子治療への臨床応用

Kawakami Yutaka

Biother Today 4 ( 2 ) 62-67 1997.12

Research paper (scientific journal), Single Work

Mart1 is located on mouse Chromosome 19 and is excluded as a candidate for ep and ru

Wright A., Kawakami Y., Pavan W.

Mammalian Genome 8 ( 5 ) 377 - 378 1997.05

ISSN 0938-8990

Access to Document (DOI)

Production of recombinant MART-1 proteins and specific anti-MART-1 polyclonal and monoclonal antibodies

Kawakami Yutaka, Battles Jane K., Kobayashi Takeshi, Ennis Willis, Wang Xiang, Tupesis Janis P., Marincola Francesco M., Robbins Paul F., Hearing Vincent J., Gonda Matthew A., Rosenberg Steven A.

Journal of Immunological Methods 202 ( 1 ) 13 - 25 1997.03

ISSN 0022-1759

Recombinant human MART-1 protein was produced by bacterial and baculoviral-insect cell expression systems. By immunization with bacterial MBP-MART-1 fusion prorein or MBP cleaved MART-1 protein, a rabbit polyclonal and two murine monoclonal antibodies specific for MART-1 were produced. These antibodies specifically detected MART-1 in immuno-precipitation, Western blotting, flow cytometric assays and in immunohistochemical analysis of tissue sections. They also stained cytoplasmic components in melanocytes and most melanoma cells in frozen or paraffin embedded tissue sections, indicating that these antibodies may be useful for the diagnosis of melanoma. One of the monoclonal antibodies M2-7 C10 recognized only human MART-1, but the other monoclonal antibody M2-9 E3 recognized both human and murine MART-1. The size of the human MART-1 molecule detected by SDS-PAGE with these antibodies was approximately 18 kDa, suggesting possible posttranslational modifications in the MART-1 protein. Subcellular fractionation studies suggested that MART-1 was present in melanosomes and endoplasmic reticulum, although known melanogenic enzymatic activities were not detected in the MART-1 protein. These reagents may be useful for biological studies on melanocytes and melanoma cells as well as for the development and monitoring of immunotherapy for patients with melanoma.

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Identification of Subdominant CTL Epitopes of the GP100 Melanoma-Associated Tumor Antigen by Primary in Vitro Immunization with Peptide-Pulsed Dendritic Cells

Tsai Van, Southwood Scott, Sidney John, Sakaguchi Kazuyasu, Kawakami Yutaka, Appella Ettore, Sette Alessandro, Celis Esteban

Journal of Immunology 158 ( 4 ) 1796 - 1802 1997.02

ISSN 0022-1767

The gp100 melanoma-associated tumor Ag was selected as a model system to study the diversity of human antitumor cytotoxic T cell responses. First, peptides corresponding to dominant gp100 HLA-A2.1-restricted CTL epitopes were tested using lymphocytes from normal volunteers and an in vitro priming protocol that uses peptide-pulsed dendritic cells as APCs and IL-7 and IL-10 as immune-enhancing cytokines. High CTL activity toward both peptide-pulsed target cells and gp100⁺ melanoma cells was obtained with four out of five peptides tested. Second, HLA-A2.1-binding peptides from gp100 that do no appear to represent CTL epitopes in melanoma patients were also tested for their capacity to induce CTL using the in vitro priming protocol. Three of six peptides tested induced CTL in lymphocytes from normal volunteers. One of these peptides was also immunogenic for lymphocytes derived from a melanoma patient in remission. Because these three CTL epitopes were not recognized in the natural immune response in melanoma patients but do appear as immunogens when peptides are used to induce the T cell response, they may be considered as typical "subdominant" epitopes. The results are discussed in the context of the usefulness of this approach to detail the immunologic potential of a given tumor-associated Ag and its relevance for the design of effective immune-based therapies.

Human tumor antigens recognized by T-cells

Kawakami Yutaka, Rosenberg Steven A.

Immunologic Research 16 ( 4 ) 313 - 339 1997

ISSN 0257-277X

T-cells play an important role in in vivo tumor rejection in many animal tumor models and in human melanoma. Many human tumor antigens recognized by autologous T-cells have now been identified. These are found to be nonmutated and mutated peptides derived from various self proteins as well as viral proteins. A variety of mechanisms involved in generating these T-cell epitopes on growing cancers have also been identified. However, the role of these identified antigens remains to be evaluated. Passive or active immunotherapies using these identified tumor antigens are being conducted in many institutions. The results obtained from these clinical trials may give us better insight into the role of T-cell responses to each antigen in tumor rejection as well as the development of new antigen-specific immunotherapies for patients with cancer.

Induction of melanoma reactive T cells by stimulator cells expressing melanoma epitope-major histocompatibility complex class I fusion proteins

Kang X., Robbins P. F., Fitzgerald E. B., Wang R. F., Rosenberg S. A., Kawakami Y.

Cancer Research 57 ( 2 ) 202 - 205 1997

ISSN 0008-5472

Several epitopes in the human melanoma antigens recognized by HLA-A2- restricted CTLs have a relatively low MHC-binding affinity and as a result may be expressed at very low densities on the cell surface, indicating that these epitopes may not be efficient immunogens. To express these epitopes at higher densities on the surface of antigen-presenting cells and therefore improve their immunogenicity, a DNA construct in which a cDNA fragment encoding the melanoma epitope MART-1_27-35 or gp100_280-288 was inserted between sequences encoding the leader and the HLA-A* 0201 protein. Cells transfected with these epitope-HLA fusion constructs were recognized by HLA-A2-restricted melanoma-reactive CTLs specific for the MART-1 or gp100 epitope. In addition, tumor-reactive CTLs could be induced from PBMCs of patients with metastatic melanoma by in vitro stimulation with HMY-C1R B- cell lines expressing the MART-1 or gp100 epitope-HLA-A* 0201 fusion protein. These epitope-HLA fusion constructs may be useful for the development of immunotherapies for patients with melanoma.

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