Cinical trial:(MDX1105-01) (Anti-PDL1)

PD-1 and CTLA-4 combination blockade expands

infiltrating T cells and reduces regulatory T and

myeloid cells within B16 melanoma tumors

http://www.box.net/shared/pupqhy4s1b

Best Regards,

Jimmy B

Douglas,

Expression of PD-L1 by uveal melanoma cells regulates T-cell function by suppressing IL-2 production. The results imply that the presence of IFN-
in the tumor local microenvironment promotes upregulation of PD-L1 expression by uveal melanoma, which may, in part, promote immune escape by impairing T-cell function. The selective blockade of PD-L1 is a potential strategy in T-cell-based immunotherapy for uveal melanoma.

Source: http://www.iovs.org/content/49/6/2518.full.pdf

Wen-Jen Hwu, MD, PhD, is a professor in the department of melanoma medical oncology at The University of Texas M.D. Anderson Cancer Center

"Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, deliver inhibitory signals that regulate the balance between T cell activation, tolerance and immunopathology. In vivo studies have shown B7-1 (CD80) is also a binding partner for PD-L1, and their interactions can lead to bidirectional inhibitory response in T cells.

PD-L1 is expressed on many tumors including melanoma and is a component of the immune suppression by the tumor microenvironment. Phase 1/2 experience of the anti-PD-1 monoclonal antibody, MDX-1106 (Medarex, Ono-4538), in refractory or relapsed malignancies was presented at the 2009 ASCO Annual Meeting. Clinical activity against melanoma was observed and, more importantly, no MDX-1106 related severe adverse events were noted.

In 2009, at M.D. Anderson Cancer Center, we participated in a phase 1 study of anti-PD-L1 monoclonal antibody (MDX-1105, Medarex) in refractory metastatic melanoma. MDX-1105 has been tolerated by all patients. Most adverse events were mild and were related to inflammatory responses in the tumors, not immune-related toxicity. Clinical responses were observed at all dose levels (1 mg/kg to 10 mg/kg every 2 weeks). Durable partial responses and stable disease were noted in patients whose disease had progressed after at least one, and as many as five, prior systemic therapies. Based on the low toxicity and impressive clinical activity, a phase 2 study of MDX-1105 in advanced melanoma is warranted.

In summary, the treatment of metastatic melanoma is changing rapidly due to the great success in translational research from bench to bedside. Although such studies, to date, have focused on the treatment of advanced metastatic disease, the approaches of targeting signal transduction pathway, as well as targeting tumor immunity barrier, hold great promise to the development of preventive strategies and personalized therapies in malignant melanoma."

Medarex /BMS

"MDX-1105 (Anti-PD-L1 Antibody)—Cancer. We are developing MDX-1105, a fully human anti-PD-L1 antibody designed to target the PD-L1 pathway to promote enhanced T-cell immune responses against cancer and reverse T-cell inactivation in chronic infectious disease. A multi-dose, dose-escalation Phase 1 trial is expected to enroll up to 46 patients with selected advanced or recurrent solid tumors (including renal cell cancer, melanoma, non-small cell lung cancer or epithelial ovarian cancer) and is designed to establish and evaluate the safety, tolerability and maximum tolerated dose, as well as preliminary pharmacodynamics and efficacy, of MDX-1105."

"We believe that our fully human anti-PD-1 and anti-PD-L1 antibodies represent the next stage in immunotherapy beyond the anti-CTLA-4 antibodies. We look forward to exploring the potential of MDX-1105 as a possible new treatment option for patients with cancer and infectious disease."

Douglas,

Expression of PD-L1 by uveal melanoma cells regulates T-cell function by suppressing IL-2 production. The results imply that the presence of IFN-
in the tumor local microenvironment promotes upregulation of PD-L1 expression by uveal melanoma, which may, in part, promote immune escape by impairing T-cell function. The selective blockade of PD-L1 is a potential strategy in T-cell-based immunotherapy for uveal melanoma.

Source: http://www.iovs.org/content/49/6/2518.full.pdf

Wen-Jen Hwu, MD, PhD, is a professor in the department of melanoma medical oncology at The University of Texas M.D. Anderson Cancer Center

"Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, deliver inhibitory signals that regulate the balance between T cell activation, tolerance and immunopathology. In vivo studies have shown B7-1 (CD80) is also a binding partner for PD-L1, and their interactions can lead to bidirectional inhibitory response in T cells.

PD-L1 is expressed on many tumors including melanoma and is a component of the immune suppression by the tumor microenvironment. Phase 1/2 experience of the anti-PD-1 monoclonal antibody, MDX-1106 (Medarex, Ono-4538), in refractory or relapsed malignancies was presented at the 2009 ASCO Annual Meeting. Clinical activity against melanoma was observed and, more importantly, no MDX-1106 related severe adverse events were noted.

In 2009, at M.D. Anderson Cancer Center, we participated in a phase 1 study of anti-PD-L1 monoclonal antibody (MDX-1105, Medarex) in refractory metastatic melanoma. MDX-1105 has been tolerated by all patients. Most adverse events were mild and were related to inflammatory responses in the tumors, not immune-related toxicity. Clinical responses were observed at all dose levels (1 mg/kg to 10 mg/kg every 2 weeks). Durable partial responses and stable disease were noted in patients whose disease had progressed after at least one, and as many as five, prior systemic therapies. Based on the low toxicity and impressive clinical activity, a phase 2 study of MDX-1105 in advanced melanoma is warranted.

In summary, the treatment of metastatic melanoma is changing rapidly due to the great success in translational research from bench to bedside. Although such studies, to date, have focused on the treatment of advanced metastatic disease, the approaches of targeting signal transduction pathway, as well as targeting tumor immunity barrier, hold great promise to the development of preventive strategies and personalized therapies in malignant melanoma."

Medarex /BMS

"MDX-1105 (Anti-PD-L1 Antibody)—Cancer. We are developing MDX-1105, a fully human anti-PD-L1 antibody designed to target the PD-L1 pathway to promote enhanced T-cell immune responses against cancer and reverse T-cell inactivation in chronic infectious disease. A multi-dose, dose-escalation Phase 1 trial is expected to enroll up to 46 patients with selected advanced or recurrent solid tumors (including renal cell cancer, melanoma, non-small cell lung cancer or epithelial ovarian cancer) and is designed to establish and evaluate the safety, tolerability and maximum tolerated dose, as well as preliminary pharmacodynamics and efficacy, of MDX-1105."

"We believe that our fully human anti-PD-1 and anti-PD-L1 antibodies represent the next stage in immunotherapy beyond the anti-CTLA-4 antibodies. We look forward to exploring the potential of MDX-1105 as a possible new treatment option for patients with cancer and infectious disease."

 Douglas,

MDX 1105 has shown higher effacacy than either MDX1106 or MDX010, according to Dr. Hwu (my former Onc).  The number of participants to date is small but very impressive. You could do a lot worse – I would do it if it were available to me.

Best Wishes,

Jim

This may be a very silly question but why is not available to you – location or eligibility requirements of the study? 

This may be a very silly question but why is not available to you – location or eligibility requirements of the study? 

 Douglas,

MDX 1105 has shown higher effacacy than either MDX1106 or MDX010, according to Dr. Hwu (my former Onc).  The number of participants to date is small but very impressive. You could do a lot worse – I would do it if it were available to me.

Best Wishes,

Jim

PD-1 and CTLA-4 combination blockade expands

infiltrating T cells and reduces regulatory T and

myeloid cells within B16 melanoma tumors

http://www.box.net/shared/pupqhy4s1b

Best Regards,

Jimmy B