A phase I trial of immunotherapy with intratumoral adenovirus-interferon-gamma (TG1041) in patients with malignant melanoma

Khorana, Alok A.; Rosenblatt, Joseph D.; Sahasrabudhe, Deepak M.; Evans, Thomas G.; Ladrigan, M.; Marquis, Diana; Rosell, Karen; Whiteside, Theresa L.; Phillippe, S.; Acres, Bruce; Seksik, Philippe; Squiban, Patrick; Ross, Mary Ellen; Kendra, Kari

doi:10.1038/sj.cgt.7700568

Cited by 62 publications

(37 citation statements)

References 38 publications

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“…Interferon beta, characterized by high tissue permeability compared to interferon alpha, showed response rates of 50 % in 10 patients [430] and markedly fewer adverse events. Khorana et al [431] conducted intratumoral adeno-interferon gamma (TG1041) therapy in 11 patients. However, this transgenic adenovirus, as vector for local interferon gamma production, did not display any noteworthy clinical events.…”

Section: Historic Proceduresmentioning

confidence: 99%

Malignant Melanoma S3‐Guideline “Diagnosis, Therapy and Follow‐up of Melanoma”

Pflugfelder

Kochs

Blum

et al. 2013

J Deutsche Derma Gesell

181

148

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Section: Historic Proceduresmentioning

confidence: 99%

Malignant Melanoma S3‐Guideline “Diagnosis, Therapy and Follow‐up of Melanoma”

Pflugfelder

Kochs

Blum

et al. 2013

J Deutsche Derma Gesell

181

148

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“…Because trials of chemotherapeutic drugs have not been satisfactory, significant interest has been directed toward immunotherapy protocols designed to induce or augment an endogenous immune response to the tumor. A variety of such clinical trials have been published, including infusions of ex vivo expanded melanoma-specific CTL (1 -4); vaccination with melanoma antigen -loaded antigen presenting cells (5 -8); transfection of tumor cells with granulocyte macrophage colony-stimulating factor (9); treatment with granulocyte macrophage colony-stimulating factor plus FLt3 ligand (10), interleukin 12 (11,12), or IFN-g (13); and, most recently, transfection of CTL with a MART-1 -specific T-cell receptor (14). Although activation of tumor-specific CTL and occasional complete clinical responses have been documented in many of these trials, they have not, in general, altered the mean survival times for the majority of patients.…”

mentioning

confidence: 99%

T-Cell Distribution and Adhesion Receptor Expression in Metastatic Melanoma

Weishaupt

Munoz

Buzney

et al. 2007

Clinical Cancer Research

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Purpose: Metastatic malignant melanoma is a devastating disease with a poor prognosis. Recent therapeutic trials have focused on immunotherapy to induce development of endogenous antitumor immune responses. To date, such protocols have shown success in activation of tumor-specific CTL but no overall improvement in survival. To kill tumor, antigen-specific CTL must efficiently target and enter tumor tissue.The purpose of this study was to examine the pathway of leukocyte migration to metastatic melanoma. Experimental design: Peripheral blood and metastatic melanoma tissues (n = 65) were evaluated for expression of adhesion molecules using immunohistochemistry of tumor sections and flow cytometry of tumor-associated and peripheral blood CTL and compared with healthy controls. CTL expressing T-cell receptors for the melanoma antigen MART-1 were identified in a subset of samples by reactivity with HLA-A2 tetramers loaded with MART-1peptide. Results: Results show that the majority of metastatic melanoma samples examined do not express the vascular adhesion receptors E-selectin (CD62E), P-selectin (CD62P), and intercellular adhesion molecule-1 (CD54) on vessels within the tumor boundaries. Strong adhesion receptor expression was noted on vessels within adjacent tissue. Tumor-associated T lymphocytes accumulate preferentially in these adjacent areas and are not enriched for skin-or lymph node^homing receptor phenotype. Conclusion: Expression of leukocyte homing receptors is dysregulated on the vasculature of metastatic melanoma. This results in a block to recruitment of activated tumor-specific CTL to melanoma metastases and is a likely factor limiting the effectiveness of current immunotherapy protocols.Despite significant effort and investment in clinical care and research, effective therapeutic options for treatment of metastatic malignant melanoma remain elusive. Because trials of chemotherapeutic drugs have not been satisfactory, significant interest has been directed toward immunotherapy protocols designed to induce or augment an endogenous immune response to the tumor. A variety of such clinical trials have been published, including infusions of ex vivo expanded melanoma-specific CTL (1 -4); vaccination with melanoma antigen -loaded antigen presenting cells (5 -8); transfection of tumor cells with granulocyte macrophage colony-stimulating factor (9); treatment with granulocyte macrophage colony-stimulating factor plus FLt3 ligand (10), interleukin 12 (11, 12), or IFN-g (13); and, most recently, transfection of CTL with a MART-1 -specific T-cell receptor (14). Although activation of tumor-specific CTL and occasional complete clinical responses have been documented in many of these trials, they have not, in general, altered the mean survival times for the majority of patients.CTL recruitment to and infiltration of metastatic tumors is an essential component of an effective immune response to melanoma. Prior studies have shown that lymphocyte infiltration is associated with spontaneous regression of primar...

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“…Clinical trials in melanoma aiming at an expression of tumor-toxic genes were reported for RD-AdVs encoding IL-24 ⁄ Mda-7 and TNF-a respectively (25,27). Other clinical trials aimed at an enhancement of the immune response as by RD-AdVs encoding for IFN-c or IL-2 (28,29). In these studies, adenoviral injections were generally well tolerated; however, the clinical efficacy was only limited.…”

Section: Discussionmentioning

confidence: 99%

Efficient and selective tumor cell lysis and induction of apoptosis in melanoma cells by a conditional replication‐competent CD95L adenovirus

Fecker

Schmude

Jost

et al. 2010

Experimental Dermatology

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The high mortality of melanoma demands the development of new strategies, and gene therapy may be considered provided improvements in efficacy and selectivity. Overexpression of the death ligand CD95L ⁄ FasL has been shown in previous studies as highly effective for apoptosis induction in melanoma cells. For efficient and selective targeting of melanoma, a conditional replication-competent adenoviral vector was constructed (Ad5-FFE-02), which drives CD95L expression by a tetracycline-inducible promoter. For restricting its replication to melanoma cells, the adenoviral E1A gene is controlled by a tyrosinase-derived promoter. Furthermore, adenoviral E1B was deleted and a mutated E1A was used to preferentially support replication in tumor cells. Proving its high selectivity and efficiency, strong expression of E1A and doxycycline-dependent induction of CD95L were characteristic for tyrosinase-positive melanoma cells after Ad5-FFE-02 transduction, whereas absent in non-melanoma cell lines. Importantly, Ad5-FFE-02-mediated cell lysis was restricted to melanoma cells, and induction of apoptosis was found only in tyrosinase and CD95 expressing cells. Finally, the combination of adenoviral replication and CD95L-mediated apoptosis resulted in an enhanced repression of melanoma cell growth. This new adenoviral vector may provide a basis for an efficient targeting of melanoma.

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A phase I trial of immunotherapy with intratumoral adenovirus-interferon-gamma (TG1041) in patients with malignant melanoma

Cited by 62 publications

References 38 publications

Malignant Melanoma S3‐Guideline “Diagnosis, Therapy and Follow‐up of Melanoma”

Malignant Melanoma S3‐Guideline “Diagnosis, Therapy and Follow‐up of Melanoma”

T-Cell Distribution and Adhesion Receptor Expression in Metastatic Melanoma

Efficient and selective tumor cell lysis and induction of apoptosis in melanoma cells by a conditional replication‐competent CD95L adenovirus

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