› Forums › General Melanoma Community › Keeping an eye out for new treatment options
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jeffjohn78.
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- March 28, 2013 at 2:27 pm
I noticed that in an earlier post a member (is that what we are?) indicated that he was having a very positive response in a trial that paired Ipi with a new compound (INCB 024360). How much promise does this approach offer– anyone know? It seems to be different than anti-PD-1 and Ipi in it’s attack objective….. I noticed that restrictions in the current trial require that you’ve had no prior treatments with immunotherapy compounds. Just wondering if there is a belief that this may eventually open up another avenue for us to follow.I noticed that in an earlier post a member (is that what we are?) indicated that he was having a very positive response in a trial that paired Ipi with a new compound (INCB 024360). How much promise does this approach offer– anyone know? It seems to be different than anti-PD-1 and Ipi in it’s attack objective….. I noticed that restrictions in the current trial require that you’ve had no prior treatments with immunotherapy compounds. Just wondering if there is a belief that this may eventually open up another avenue for us to follow. I myself am in an anti- PD-1 trial –but it would be nice to know that the arsenal I may eventually need to rely on is growing.
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- March 28, 2013 at 3:35 pm
Indoleamine 2,3-dioxygenase-1 (IDO1; IDO) mediates oxidative cleavage of tryptophan, an amino acid essential for cell proliferation and survival. IDO1 inhibition is proposed to have therapeutic potential in immunodeficiency-associated abnormalities, including cancer. Here, we describe INCB024360, a novel IDO1 inhibitor, and investigate its roles in regulating various immune cells and therapeutic potential as an anticancer agent. In cellular assays, INCB024360 selectively inhibits human IDO1 with IC50 values of approximately 10nM, demonstrating little activity against other related enzymes such as IDO2 or tryptophan 2,3-dioxygenase (TDO). In coculture systems of human allogeneic lymphocytes with dendritic cells (DCs) or tumor cells, INCB024360 inhibition of IDO1 promotes T and natural killer (NK)–cell growth, increases IFN-γ production, and reduces conversion to regulatory T (Treg)–like cells. IDO1 induction triggers DC apoptosis, whereas INCB024360 reverses this and increases the number of CD86high DCs, potentially representing a novel mechanism by which IDO1 inhibition activates T cells. Furthermore, IDO1 regulation differs in DCs versus tumor cells. Consistent with its effects in vitro, administration of INCB024360 to tumor-bearing mice significantly inhibits tumor growth in a lymphocyte-dependent manner. Analysis of plasma kynurenine/tryptophan levels in patients with cancer affirms that the IDO pathway is activated in multiple tumor types. Collectively, the data suggest that selective inhibition of IDO1 may represent an attractive cancer therapeutic strategy via up-regulation of cellular immunity. -
- March 28, 2013 at 3:35 pm
Indoleamine 2,3-dioxygenase-1 (IDO1; IDO) mediates oxidative cleavage of tryptophan, an amino acid essential for cell proliferation and survival. IDO1 inhibition is proposed to have therapeutic potential in immunodeficiency-associated abnormalities, including cancer. Here, we describe INCB024360, a novel IDO1 inhibitor, and investigate its roles in regulating various immune cells and therapeutic potential as an anticancer agent. In cellular assays, INCB024360 selectively inhibits human IDO1 with IC50 values of approximately 10nM, demonstrating little activity against other related enzymes such as IDO2 or tryptophan 2,3-dioxygenase (TDO). In coculture systems of human allogeneic lymphocytes with dendritic cells (DCs) or tumor cells, INCB024360 inhibition of IDO1 promotes T and natural killer (NK)–cell growth, increases IFN-γ production, and reduces conversion to regulatory T (Treg)–like cells. IDO1 induction triggers DC apoptosis, whereas INCB024360 reverses this and increases the number of CD86high DCs, potentially representing a novel mechanism by which IDO1 inhibition activates T cells. Furthermore, IDO1 regulation differs in DCs versus tumor cells. Consistent with its effects in vitro, administration of INCB024360 to tumor-bearing mice significantly inhibits tumor growth in a lymphocyte-dependent manner. Analysis of plasma kynurenine/tryptophan levels in patients with cancer affirms that the IDO pathway is activated in multiple tumor types. Collectively, the data suggest that selective inhibition of IDO1 may represent an attractive cancer therapeutic strategy via up-regulation of cellular immunity.-
- March 28, 2013 at 4:39 pm
Indoleamine 2, 3-dioxygenase (IDO) is an immune regulatory enzyme that is normally expressed in tumor cells and in activated immune cells. It dampens the immune response through oxidation of tryptophan, thereby blocking T-cell activation and inducing T-cell apoptosis. This creates an environment in which tumor-specific cytotoxic T lymphocytes are rendered functionally inactive or are no longer able to attack a patient’s cancer cells. Preclinical studies have shown that inhibition of IDO increases the anti-tumor immune response and dramatically increases the efficacy of various chemotherapeutic agents.Hopfully the drug will increase the response rate when combined with Yervoy
The Phase I dose-escalation trial of INCB24360, a novel oral inhibitor of IDO, has achieved its objective in selecting a dose that is generally well-tolerated and potently inhibits the target as measured using two independent pharmacodynamic markers. “Pharmacodynamic assessment of INCB242360, an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), in advanced cancer patients” was the subject of an oral presentation at the 2012 American Society of Clinical Oncology annual meeting.
The first Phase II study of INCB24360, which was initiated in 2012, is a randomized study in combination with ipilimumab in patients with metastatic melanoma (www.clinicaltrials.gov Identifier: NCT01604889).
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- March 28, 2013 at 11:14 pm
How Aging Reduces Tryptophan-Serotonin LevelsAs a result of normal aging, inflammatory cytokine levels increase. A little-known adverse effect is that inflammatory cytokines (such as tumor necrosis factor alpha and interferon alpha) cause induction of the tryptophan-degrading enzyme IDO (indoleamine 2,3-dioxygenase).
You might think that aging people could compensate for the tryptophan-degrading effects of IDO by consuming higher doses of tryptophan supplements. The problem is that in the presence of high blood levels of tryptophan, the other tryptophan-degrading enzyme TDO is also elevated.
So consuming large amounts of L-tryptophan (oral doses of 4,000 mg and greater) will not generate more serotonin because TDO will be induced. Yet if aging people fail to get more tryptophan into their bodies, brain serotonin levels will plummet because the higher IDO enzyme activity will degrade what little tryptophan remains in the blood.
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- March 28, 2013 at 11:14 pm
How Aging Reduces Tryptophan-Serotonin LevelsAs a result of normal aging, inflammatory cytokine levels increase. A little-known adverse effect is that inflammatory cytokines (such as tumor necrosis factor alpha and interferon alpha) cause induction of the tryptophan-degrading enzyme IDO (indoleamine 2,3-dioxygenase).
You might think that aging people could compensate for the tryptophan-degrading effects of IDO by consuming higher doses of tryptophan supplements. The problem is that in the presence of high blood levels of tryptophan, the other tryptophan-degrading enzyme TDO is also elevated.
So consuming large amounts of L-tryptophan (oral doses of 4,000 mg and greater) will not generate more serotonin because TDO will be induced. Yet if aging people fail to get more tryptophan into their bodies, brain serotonin levels will plummet because the higher IDO enzyme activity will degrade what little tryptophan remains in the blood.
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- March 28, 2013 at 11:14 pm
How Aging Reduces Tryptophan-Serotonin LevelsAs a result of normal aging, inflammatory cytokine levels increase. A little-known adverse effect is that inflammatory cytokines (such as tumor necrosis factor alpha and interferon alpha) cause induction of the tryptophan-degrading enzyme IDO (indoleamine 2,3-dioxygenase).
You might think that aging people could compensate for the tryptophan-degrading effects of IDO by consuming higher doses of tryptophan supplements. The problem is that in the presence of high blood levels of tryptophan, the other tryptophan-degrading enzyme TDO is also elevated.
So consuming large amounts of L-tryptophan (oral doses of 4,000 mg and greater) will not generate more serotonin because TDO will be induced. Yet if aging people fail to get more tryptophan into their bodies, brain serotonin levels will plummet because the higher IDO enzyme activity will degrade what little tryptophan remains in the blood.
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- March 28, 2013 at 4:39 pm
Indoleamine 2, 3-dioxygenase (IDO) is an immune regulatory enzyme that is normally expressed in tumor cells and in activated immune cells. It dampens the immune response through oxidation of tryptophan, thereby blocking T-cell activation and inducing T-cell apoptosis. This creates an environment in which tumor-specific cytotoxic T lymphocytes are rendered functionally inactive or are no longer able to attack a patient’s cancer cells. Preclinical studies have shown that inhibition of IDO increases the anti-tumor immune response and dramatically increases the efficacy of various chemotherapeutic agents.Hopfully the drug will increase the response rate when combined with Yervoy
The Phase I dose-escalation trial of INCB24360, a novel oral inhibitor of IDO, has achieved its objective in selecting a dose that is generally well-tolerated and potently inhibits the target as measured using two independent pharmacodynamic markers. “Pharmacodynamic assessment of INCB242360, an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), in advanced cancer patients” was the subject of an oral presentation at the 2012 American Society of Clinical Oncology annual meeting.
The first Phase II study of INCB24360, which was initiated in 2012, is a randomized study in combination with ipilimumab in patients with metastatic melanoma (www.clinicaltrials.gov Identifier: NCT01604889).
-
- March 28, 2013 at 4:39 pm
Indoleamine 2, 3-dioxygenase (IDO) is an immune regulatory enzyme that is normally expressed in tumor cells and in activated immune cells. It dampens the immune response through oxidation of tryptophan, thereby blocking T-cell activation and inducing T-cell apoptosis. This creates an environment in which tumor-specific cytotoxic T lymphocytes are rendered functionally inactive or are no longer able to attack a patient’s cancer cells. Preclinical studies have shown that inhibition of IDO increases the anti-tumor immune response and dramatically increases the efficacy of various chemotherapeutic agents.Hopfully the drug will increase the response rate when combined with Yervoy
The Phase I dose-escalation trial of INCB24360, a novel oral inhibitor of IDO, has achieved its objective in selecting a dose that is generally well-tolerated and potently inhibits the target as measured using two independent pharmacodynamic markers. “Pharmacodynamic assessment of INCB242360, an inhibitor of indoleamine 2,3-dioxygenase 1 (IDO1), in advanced cancer patients” was the subject of an oral presentation at the 2012 American Society of Clinical Oncology annual meeting.
The first Phase II study of INCB24360, which was initiated in 2012, is a randomized study in combination with ipilimumab in patients with metastatic melanoma (www.clinicaltrials.gov Identifier: NCT01604889).
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- March 28, 2013 at 3:35 pm
Indoleamine 2,3-dioxygenase-1 (IDO1; IDO) mediates oxidative cleavage of tryptophan, an amino acid essential for cell proliferation and survival. IDO1 inhibition is proposed to have therapeutic potential in immunodeficiency-associated abnormalities, including cancer. Here, we describe INCB024360, a novel IDO1 inhibitor, and investigate its roles in regulating various immune cells and therapeutic potential as an anticancer agent. In cellular assays, INCB024360 selectively inhibits human IDO1 with IC50 values of approximately 10nM, demonstrating little activity against other related enzymes such as IDO2 or tryptophan 2,3-dioxygenase (TDO). In coculture systems of human allogeneic lymphocytes with dendritic cells (DCs) or tumor cells, INCB024360 inhibition of IDO1 promotes T and natural killer (NK)–cell growth, increases IFN-γ production, and reduces conversion to regulatory T (Treg)–like cells. IDO1 induction triggers DC apoptosis, whereas INCB024360 reverses this and increases the number of CD86high DCs, potentially representing a novel mechanism by which IDO1 inhibition activates T cells. Furthermore, IDO1 regulation differs in DCs versus tumor cells. Consistent with its effects in vitro, administration of INCB024360 to tumor-bearing mice significantly inhibits tumor growth in a lymphocyte-dependent manner. Analysis of plasma kynurenine/tryptophan levels in patients with cancer affirms that the IDO pathway is activated in multiple tumor types. Collectively, the data suggest that selective inhibition of IDO1 may represent an attractive cancer therapeutic strategy via up-regulation of cellular immunity. -
- March 29, 2013 at 4:38 am
Hi there!
I am the member who posted about successful results from this Ipi -INCB 024360 trail from Incyte. I have had great results as mentioned…I had 5 tumors including 2 in the brain…3 of the 5 are completly gone including both in the brain, the other 2 are shrinking as well.
This is very early in the trial…I was the 2nd patient in the trial and to my knowledge their is only 5 of us as of today. The issue seems to be a high level of liver toxicity this trial drug causes. The trial originally started at doses of 300 mg twice a day. Patients had very high liver toxicity with multple hospitalizations I believe. The FDA then stopped the trial. Itwas later reopened but the dosage of the trial drug was lowered to only 25 mg twice daily, which is what I am taking.
I also have to have weekly blood tests and if any mesurements that have to do with liver functionality (including ones that are normally ignored regardess of how out of whack they are) show abnormality, I have to go get a 2nd blood test that week. I have had to get the 2nd blood test a few times, but fortunetly have never had succesive "funny" blood tests, so I can't say what would happen if you have more then 1 test in a row showup with abnormalities.
I am also aware that 1 of the other 4 patients who started the trial has since been removed to the trial since he has been hospitalized twice. I belive the hospitalizations were related t his rections to the ipi though, but he was removed none the less.
This trial is run out of the Angeles Clinic in West Los Angeles.
My email is [email protected], feel free to contact me if I havent answered all your quesions and good luck in your fight!
Jeff
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- March 29, 2013 at 4:38 am
Hi there!
I am the member who posted about successful results from this Ipi -INCB 024360 trail from Incyte. I have had great results as mentioned…I had 5 tumors including 2 in the brain…3 of the 5 are completly gone including both in the brain, the other 2 are shrinking as well.
This is very early in the trial…I was the 2nd patient in the trial and to my knowledge their is only 5 of us as of today. The issue seems to be a high level of liver toxicity this trial drug causes. The trial originally started at doses of 300 mg twice a day. Patients had very high liver toxicity with multple hospitalizations I believe. The FDA then stopped the trial. Itwas later reopened but the dosage of the trial drug was lowered to only 25 mg twice daily, which is what I am taking.
I also have to have weekly blood tests and if any mesurements that have to do with liver functionality (including ones that are normally ignored regardess of how out of whack they are) show abnormality, I have to go get a 2nd blood test that week. I have had to get the 2nd blood test a few times, but fortunetly have never had succesive "funny" blood tests, so I can't say what would happen if you have more then 1 test in a row showup with abnormalities.
I am also aware that 1 of the other 4 patients who started the trial has since been removed to the trial since he has been hospitalized twice. I belive the hospitalizations were related t his rections to the ipi though, but he was removed none the less.
This trial is run out of the Angeles Clinic in West Los Angeles.
My email is [email protected], feel free to contact me if I havent answered all your quesions and good luck in your fight!
Jeff
-
- March 29, 2013 at 4:38 am
Hi there!
I am the member who posted about successful results from this Ipi -INCB 024360 trail from Incyte. I have had great results as mentioned…I had 5 tumors including 2 in the brain…3 of the 5 are completly gone including both in the brain, the other 2 are shrinking as well.
This is very early in the trial…I was the 2nd patient in the trial and to my knowledge their is only 5 of us as of today. The issue seems to be a high level of liver toxicity this trial drug causes. The trial originally started at doses of 300 mg twice a day. Patients had very high liver toxicity with multple hospitalizations I believe. The FDA then stopped the trial. Itwas later reopened but the dosage of the trial drug was lowered to only 25 mg twice daily, which is what I am taking.
I also have to have weekly blood tests and if any mesurements that have to do with liver functionality (including ones that are normally ignored regardess of how out of whack they are) show abnormality, I have to go get a 2nd blood test that week. I have had to get the 2nd blood test a few times, but fortunetly have never had succesive "funny" blood tests, so I can't say what would happen if you have more then 1 test in a row showup with abnormalities.
I am also aware that 1 of the other 4 patients who started the trial has since been removed to the trial since he has been hospitalized twice. I belive the hospitalizations were related t his rections to the ipi though, but he was removed none the less.
This trial is run out of the Angeles Clinic in West Los Angeles.
My email is [email protected], feel free to contact me if I havent answered all your quesions and good luck in your fight!
Jeff
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