Prevention of Interleukin-2 Withdrawal-Induced Apoptosis in Lymphocytes Retrovirally Cotransduced With Genes Encoding an Antitumor T-cell Receptor and an Antiapoptotic Protein
Adoptive cell transfer using autologous tumor infiltrating lymphocytes or lymphocytes transduced with antitumor T-cell receptor (TCR) is an effective therapy for patients with metastatic melanoma. A limiting factor in the effectiveness of this treatment is the apoptosis of the transferred cells when...
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| Veröffentlicht in: | Journal of immunotherapy 2010-09, Vol.33 (7), p.672-683 |
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| creator | KALBASI, Anusha SHRIMALI, Rajeev K CHINNASAMY, Dhanalakshmi ROSENBERG, Steven A |
| description | Adoptive cell transfer using autologous tumor infiltrating lymphocytes or lymphocytes transduced with antitumor T-cell receptor (TCR) is an effective therapy for patients with metastatic melanoma. A limiting factor in the effectiveness of this treatment is the apoptosis of the transferred cells when Interleukin-2 (IL-2) administration is withdrawn. In an attempt to improve persistence of the transferred lymphocytes, we cotransduced human peripheral blood lymphocytes with retroviruses encoding Bcl-2 or Bcl-xL, antiapoptotic genes of the BCL2 family, and the MART-1 melanoma tumor antigen-specific TCR, DMF5. Lymphocytes were cotransduced with 38% to 64% cotransduction efficiency, and exhibited a marked delay in apoptosis after IL-2 withdrawal. Cotransduction with Bcl-2 or Bcl-xL did not affect cytokine secretion or lytic ability of the DMF5-transduced lymphocytes. After 5 days of IL-2 withdrawal, cotransduced lymphocytes produced similar levels of IFN-γ per cell as DMF5-alone transduced lymphocytes in response to tumor cells. Cotransduction did not alter the phenotype of lymphocytes with respect to a panel of T-cell differentiation markers. In a mouse model of melanoma, adoptively transferred T cells transduced with Bcl-2 persisted better in vivo at the site of tumor, 13 and 21 days after adoptive transfer (P=0.0064 and 0.041, respectively), with evidence of enrichment of the Bcl-2-transduced population over time (P |
| doi_str_mv | 10.1097/CJI.0b013e3181e475cd |
| format | Article |
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A limiting factor in the effectiveness of this treatment is the apoptosis of the transferred cells when Interleukin-2 (IL-2) administration is withdrawn. In an attempt to improve persistence of the transferred lymphocytes, we cotransduced human peripheral blood lymphocytes with retroviruses encoding Bcl-2 or Bcl-xL, antiapoptotic genes of the BCL2 family, and the MART-1 melanoma tumor antigen-specific TCR, DMF5. Lymphocytes were cotransduced with 38% to 64% cotransduction efficiency, and exhibited a marked delay in apoptosis after IL-2 withdrawal. Cotransduction with Bcl-2 or Bcl-xL did not affect cytokine secretion or lytic ability of the DMF5-transduced lymphocytes. After 5 days of IL-2 withdrawal, cotransduced lymphocytes produced similar levels of IFN-γ per cell as DMF5-alone transduced lymphocytes in response to tumor cells. Cotransduction did not alter the phenotype of lymphocytes with respect to a panel of T-cell differentiation markers. In a mouse model of melanoma, adoptively transferred T cells transduced with Bcl-2 persisted better in vivo at the site of tumor, 13 and 21 days after adoptive transfer (P=0.0064 and 0.041, respectively), with evidence of enrichment of the Bcl-2-transduced population over time (P<0.0001). Thus, by coexpressing Bcl-2 or Bcl-xL with a tumor-specific TCR, we have engineered a lymphocyte that resists apoptosis owing to IL-2 withdrawal without altering its tumor-specific function or phenotype, and thus may show improved antitumor effectiveness in vivo after cell transfer.</description><identifier>ISSN: 1524-9557</identifier><identifier>ISSN: 1053-8550</identifier><identifier>EISSN: 1537-4513</identifier><identifier>DOI: 10.1097/CJI.0b013e3181e475cd</identifier><identifier>PMID: 20664359</identifier><identifier>CODEN: JOIMF8</identifier><language>eng</language><publisher>Hagerstown, MD: Lippincott Williams & Wilkins</publisher><subject>Adoptive Transfer ; Animals ; Antigens, Differentiation - metabolism ; Antineoplastic agents ; Apoptosis - drug effects ; Apoptosis - genetics ; Biological and medical sciences ; Cancer Vaccines ; Cell Survival - genetics ; Dermatology ; Genetic Engineering ; Humans ; Immunotherapy ; Immunotherapy, Adoptive ; Interferon-gamma - metabolism ; Interleukin-2 - pharmacology ; MART-1 Antigen - immunology ; Medical sciences ; Melanoma - immunology ; Melanoma - therapy ; Melanoma, Experimental ; Mice ; Mice, Inbred C57BL ; Pharmacology. Drug treatments ; Proto-Oncogene Proteins c-bcl-2 - genetics ; Proto-Oncogene Proteins c-bcl-2 - immunology ; Proto-Oncogene Proteins c-bcl-2 - metabolism ; Receptors, Antigen, T-Cell - genetics ; Receptors, Antigen, T-Cell - immunology ; Receptors, Antigen, T-Cell - metabolism ; Retroviridae - genetics ; Retrovirus ; T-Lymphocytes - drug effects ; T-Lymphocytes - immunology ; T-Lymphocytes - metabolism ; T-Lymphocytes - pathology ; Tumors of the skin and soft tissue. Premalignant lesions</subject><ispartof>Journal of immunotherapy, 2010-09, Vol.33 (7), p.672-683</ispartof><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c552t-276f5da4e0a7a1872c40af45c3007c2085eea4002eaa0a9a31a819868bb8dd373</citedby><cites>FETCH-LOGICAL-c552t-276f5da4e0a7a1872c40af45c3007c2085eea4002eaa0a9a31a819868bb8dd373</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23083115$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20664359$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>KALBASI, Anusha</creatorcontrib><creatorcontrib>SHRIMALI, Rajeev K</creatorcontrib><creatorcontrib>CHINNASAMY, Dhanalakshmi</creatorcontrib><creatorcontrib>ROSENBERG, Steven A</creatorcontrib><title>Prevention of Interleukin-2 Withdrawal-Induced Apoptosis in Lymphocytes Retrovirally Cotransduced With Genes Encoding an Antitumor T-cell Receptor and an Antiapoptotic Protein</title><title>Journal of immunotherapy</title><addtitle>J Immunother</addtitle><description>Adoptive cell transfer using autologous tumor infiltrating lymphocytes or lymphocytes transduced with antitumor T-cell receptor (TCR) is an effective therapy for patients with metastatic melanoma. A limiting factor in the effectiveness of this treatment is the apoptosis of the transferred cells when Interleukin-2 (IL-2) administration is withdrawn. In an attempt to improve persistence of the transferred lymphocytes, we cotransduced human peripheral blood lymphocytes with retroviruses encoding Bcl-2 or Bcl-xL, antiapoptotic genes of the BCL2 family, and the MART-1 melanoma tumor antigen-specific TCR, DMF5. Lymphocytes were cotransduced with 38% to 64% cotransduction efficiency, and exhibited a marked delay in apoptosis after IL-2 withdrawal. Cotransduction with Bcl-2 or Bcl-xL did not affect cytokine secretion or lytic ability of the DMF5-transduced lymphocytes. After 5 days of IL-2 withdrawal, cotransduced lymphocytes produced similar levels of IFN-γ per cell as DMF5-alone transduced lymphocytes in response to tumor cells. Cotransduction did not alter the phenotype of lymphocytes with respect to a panel of T-cell differentiation markers. In a mouse model of melanoma, adoptively transferred T cells transduced with Bcl-2 persisted better in vivo at the site of tumor, 13 and 21 days after adoptive transfer (P=0.0064 and 0.041, respectively), with evidence of enrichment of the Bcl-2-transduced population over time (P<0.0001). Thus, by coexpressing Bcl-2 or Bcl-xL with a tumor-specific TCR, we have engineered a lymphocyte that resists apoptosis owing to IL-2 withdrawal without altering its tumor-specific function or phenotype, and thus may show improved antitumor effectiveness in vivo after cell transfer.</description><subject>Adoptive Transfer</subject><subject>Animals</subject><subject>Antigens, Differentiation - metabolism</subject><subject>Antineoplastic agents</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - genetics</subject><subject>Biological and medical sciences</subject><subject>Cancer Vaccines</subject><subject>Cell Survival - genetics</subject><subject>Dermatology</subject><subject>Genetic Engineering</subject><subject>Humans</subject><subject>Immunotherapy</subject><subject>Immunotherapy, Adoptive</subject><subject>Interferon-gamma - metabolism</subject><subject>Interleukin-2 - pharmacology</subject><subject>MART-1 Antigen - immunology</subject><subject>Medical sciences</subject><subject>Melanoma - immunology</subject><subject>Melanoma - therapy</subject><subject>Melanoma, Experimental</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Pharmacology. Drug treatments</subject><subject>Proto-Oncogene Proteins c-bcl-2 - genetics</subject><subject>Proto-Oncogene Proteins c-bcl-2 - immunology</subject><subject>Proto-Oncogene Proteins c-bcl-2 - metabolism</subject><subject>Receptors, Antigen, T-Cell - genetics</subject><subject>Receptors, Antigen, T-Cell - immunology</subject><subject>Receptors, Antigen, T-Cell - metabolism</subject><subject>Retroviridae - genetics</subject><subject>Retrovirus</subject><subject>T-Lymphocytes - drug effects</subject><subject>T-Lymphocytes - immunology</subject><subject>T-Lymphocytes - metabolism</subject><subject>T-Lymphocytes - pathology</subject><subject>Tumors of the skin and soft tissue. Premalignant lesions</subject><issn>1524-9557</issn><issn>1053-8550</issn><issn>1537-4513</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFks9uEzEQxlcIREvhDRDyBfW0xV7ba-8FKYpKCYpEhYo4ribe2cawsYPtDcpT8Yp4SVr-XHqyJf_mG38zX1G8ZPSC0Ua9mX9YXNAVZRw50wyFkqZ7VJwyyVUpJOOPp3slykZKdVI8i_ErpVVdieppcVLRuhZcNqfFz-uAO3TJekd8TxYuYRhw_GZdWZEvNq27AD9gKBeuGw12ZLb12-SjjcQ6stxvtmtv9gkj-YQp-J0NMAx7MvcpgIuHkkmFXKHL0KUzvrPuloAjs9w0jRsfyE1pcBiygsGsHfJjdwfA73bJGnIdfELrnhdPehgivjieZ8Xnd5c38_fl8uPVYj5blkbKKpWVqnvZgUAKCphWlREUeiENp1SZimqJCCIPBAEoNMAZaNboWq9Wuuu44mfF24PudlxtsDN5RNlauw12A2HferDtvy_Orttbv2tr3tBGTgLnR4Hgv48YU7uxcfIJDv0YW11XSgvN64dJpmqWV84fJJXQTXZeT5riQJrgYwzY3_-c0XaKT5vj0_4fn1z26m_X90V3ecnA6yMA0cDQ5y0bG_9wnGrOcgR_ARr306w</recordid><startdate>20100901</startdate><enddate>20100901</enddate><creator>KALBASI, Anusha</creator><creator>SHRIMALI, Rajeev K</creator><creator>CHINNASAMY, Dhanalakshmi</creator><creator>ROSENBERG, Steven A</creator><general>Lippincott Williams & Wilkins</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7T5</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7T7</scope><scope>C1K</scope><scope>5PM</scope></search><sort><creationdate>20100901</creationdate><title>Prevention of Interleukin-2 Withdrawal-Induced Apoptosis in Lymphocytes Retrovirally Cotransduced With Genes Encoding an Antitumor T-cell Receptor and an Antiapoptotic Protein</title><author>KALBASI, Anusha ; SHRIMALI, Rajeev K ; CHINNASAMY, Dhanalakshmi ; ROSENBERG, Steven A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c552t-276f5da4e0a7a1872c40af45c3007c2085eea4002eaa0a9a31a819868bb8dd373</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Adoptive Transfer</topic><topic>Animals</topic><topic>Antigens, Differentiation - metabolism</topic><topic>Antineoplastic agents</topic><topic>Apoptosis - drug effects</topic><topic>Apoptosis - genetics</topic><topic>Biological and medical sciences</topic><topic>Cancer Vaccines</topic><topic>Cell Survival - genetics</topic><topic>Dermatology</topic><topic>Genetic Engineering</topic><topic>Humans</topic><topic>Immunotherapy</topic><topic>Immunotherapy, Adoptive</topic><topic>Interferon-gamma - metabolism</topic><topic>Interleukin-2 - pharmacology</topic><topic>MART-1 Antigen - immunology</topic><topic>Medical sciences</topic><topic>Melanoma - immunology</topic><topic>Melanoma - therapy</topic><topic>Melanoma, Experimental</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Pharmacology. Drug treatments</topic><topic>Proto-Oncogene Proteins c-bcl-2 - genetics</topic><topic>Proto-Oncogene Proteins c-bcl-2 - immunology</topic><topic>Proto-Oncogene Proteins c-bcl-2 - metabolism</topic><topic>Receptors, Antigen, T-Cell - genetics</topic><topic>Receptors, Antigen, T-Cell - immunology</topic><topic>Receptors, Antigen, T-Cell - metabolism</topic><topic>Retroviridae - genetics</topic><topic>Retrovirus</topic><topic>T-Lymphocytes - drug effects</topic><topic>T-Lymphocytes - immunology</topic><topic>T-Lymphocytes - metabolism</topic><topic>T-Lymphocytes - pathology</topic><topic>Tumors of the skin and soft tissue. 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A limiting factor in the effectiveness of this treatment is the apoptosis of the transferred cells when Interleukin-2 (IL-2) administration is withdrawn. In an attempt to improve persistence of the transferred lymphocytes, we cotransduced human peripheral blood lymphocytes with retroviruses encoding Bcl-2 or Bcl-xL, antiapoptotic genes of the BCL2 family, and the MART-1 melanoma tumor antigen-specific TCR, DMF5. Lymphocytes were cotransduced with 38% to 64% cotransduction efficiency, and exhibited a marked delay in apoptosis after IL-2 withdrawal. Cotransduction with Bcl-2 or Bcl-xL did not affect cytokine secretion or lytic ability of the DMF5-transduced lymphocytes. After 5 days of IL-2 withdrawal, cotransduced lymphocytes produced similar levels of IFN-γ per cell as DMF5-alone transduced lymphocytes in response to tumor cells. Cotransduction did not alter the phenotype of lymphocytes with respect to a panel of T-cell differentiation markers. In a mouse model of melanoma, adoptively transferred T cells transduced with Bcl-2 persisted better in vivo at the site of tumor, 13 and 21 days after adoptive transfer (P=0.0064 and 0.041, respectively), with evidence of enrichment of the Bcl-2-transduced population over time (P<0.0001). Thus, by coexpressing Bcl-2 or Bcl-xL with a tumor-specific TCR, we have engineered a lymphocyte that resists apoptosis owing to IL-2 withdrawal without altering its tumor-specific function or phenotype, and thus may show improved antitumor effectiveness in vivo after cell transfer.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams & Wilkins</pub><pmid>20664359</pmid><doi>10.1097/CJI.0b013e3181e475cd</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of immunotherapy, 2010-09, Vol.33 (7), p.672-683 |
| issn | 1524-9557 1053-8550 1537-4513 |
| language | eng |
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| source | MEDLINE; Journals@Ovid Complete |
| subjects | Adoptive Transfer Animals Antigens, Differentiation - metabolism Antineoplastic agents Apoptosis - drug effects Apoptosis - genetics Biological and medical sciences Cancer Vaccines Cell Survival - genetics Dermatology Genetic Engineering Humans Immunotherapy Immunotherapy, Adoptive Interferon-gamma - metabolism Interleukin-2 - pharmacology MART-1 Antigen - immunology Medical sciences Melanoma - immunology Melanoma - therapy Melanoma, Experimental Mice Mice, Inbred C57BL Pharmacology. Drug treatments Proto-Oncogene Proteins c-bcl-2 - genetics Proto-Oncogene Proteins c-bcl-2 - immunology Proto-Oncogene Proteins c-bcl-2 - metabolism Receptors, Antigen, T-Cell - genetics Receptors, Antigen, T-Cell - immunology Receptors, Antigen, T-Cell - metabolism Retroviridae - genetics Retrovirus T-Lymphocytes - drug effects T-Lymphocytes - immunology T-Lymphocytes - metabolism T-Lymphocytes - pathology Tumors of the skin and soft tissue. Premalignant lesions |
| title | Prevention of Interleukin-2 Withdrawal-Induced Apoptosis in Lymphocytes Retrovirally Cotransduced With Genes Encoding an Antitumor T-cell Receptor and an Antiapoptotic Protein |
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