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Inflammation points the way to new target in solid tumors
NEW YORK – Inflammation is a hallmark of solid tumors, and chronic inflammation is a key regulator of T cell biology and therapeutic response in cancer. Bruton’s tyrosine kinase (BTK), a target in blood cancers for BTK inhibitors such as ibrutinib (Imbruvica), also poses a promising means to modulate humoral immunity and quiet a tumorigenic environment in solid tumors.
At the first International Cancer Immunotherapy Conference, Lisa Coussens, Ph.D., professor and chair of the department of cell, developmental, and cancer biology at Oregon Health Sciences University and associate director of basic research at Knight Cancer Institute, Portland (Ore.), provided a background and summarized how she and collaborators are working to limit B cell activity through inhibiting BTK.
BTK is an enzyme that plays a role both in B cell maturation and mast cell activation. Dr. Coussens, noting the importance of humoral immunity in many cancers, cited the work of Karin de Visser, Ph.D., among other researchers, who has found that circulating immune complexes can be angiogenic and tumorigenic.
In particular, the T helper-2 pathway (Th2), to a much greater extent than the Th1 pathway, can be proangiogenic, profibrotic, and immune suppressive. In cancer, when this pathway is unregulated, it “lets a tumor grow and be bad,” said Dr. Coussens.
Dr. Coussens said that Dr. de Visser’s work asks the key question: “If we depleted B cells, could we abate this pathway?”
The mechanism by which T cells are suppressed, she said, is tissue specific rather than oncogene specific. Mouse models of mammary adenocarcinoma, squamous cell carcinoma, and non–small cell lung adenocarcinoma have helped elaborate the importance of blocking the Th2 phenotype or promoting the Th1 pathway, resulting in CD8+ T cell mobilization. When the balance shifts to a Th1-predominant milieu, said Dr. Coussens, the host environment becomes angiostatic, immunostimulatory, and ultimately antitumorigenic.
In humans with chronic lymphocytic leukemia, the BTK pathway is activated in B cells and in the myeloid compartment. BTK inhibitors such as ibrutinib are currently in use for lymphomas and chronic lymphocytic leukemia.
Though BTK positive cells are also seen in pancreatic cancer. Dr. Coussens said that pancreatic cancer had been considered largely immunologically inert until recently, when researchers have begun to pay more attention to humoral immunity in the disease. However, asked Dr. Coussens, “Does the humorally mediated signature appear as a tractable target?”
To help answer the question, Dr. Coussens and her collaborators have recently shown that BTK inhibition improves response to gemcitabine in pancreatic cancer in a mouse model. Mice with an induced pancreatic tumor received the BTK inhibitor (BTKi) termed ACP-196 alone, gemcitabine alone, both, or neither. After 28 days, the combination group had significantly smaller tumor size than any other group.
Decreased desmoplasia was seen in tumor pathology when gemcitabine was combined with another BTKi, ibrutinib, said Dr. Coussens. An early dosing strategy, she said, shows that BTKi can also be effective as monotherapy when begun early enough in both tumor models studied.
Current clinical trials are underway investigating BTK inhibition in combination with conventional chemotherapy for pancreatic duct adenocarcinoma, as well as for head and neck squamous cell carcinoma.
Potential mechanisms for the promising efficacy of BTK inhibition in solid tumors include regulation of macrophage adhesion to the extracellular matrix, with suppressed adhesion to VCAM-1, and suppressed integrin activation. “Tumors are quite likely dying as a consequence of failure to adhere outside of the tumor environment,” said Dr. Coussens.
Dr. Coussens reported being on the advisory boards of Pharmacyclics Inc (the manufacturer of ibrutinib); AstraZeneca; Cellgene; and Five Prime. She receives research support from multiple pharmaceutical companies.
On Twitter @karioakes
NEW YORK – Inflammation is a hallmark of solid tumors, and chronic inflammation is a key regulator of T cell biology and therapeutic response in cancer. Bruton’s tyrosine kinase (BTK), a target in blood cancers for BTK inhibitors such as ibrutinib (Imbruvica), also poses a promising means to modulate humoral immunity and quiet a tumorigenic environment in solid tumors.
At the first International Cancer Immunotherapy Conference, Lisa Coussens, Ph.D., professor and chair of the department of cell, developmental, and cancer biology at Oregon Health Sciences University and associate director of basic research at Knight Cancer Institute, Portland (Ore.), provided a background and summarized how she and collaborators are working to limit B cell activity through inhibiting BTK.
BTK is an enzyme that plays a role both in B cell maturation and mast cell activation. Dr. Coussens, noting the importance of humoral immunity in many cancers, cited the work of Karin de Visser, Ph.D., among other researchers, who has found that circulating immune complexes can be angiogenic and tumorigenic.
In particular, the T helper-2 pathway (Th2), to a much greater extent than the Th1 pathway, can be proangiogenic, profibrotic, and immune suppressive. In cancer, when this pathway is unregulated, it “lets a tumor grow and be bad,” said Dr. Coussens.
Dr. Coussens said that Dr. de Visser’s work asks the key question: “If we depleted B cells, could we abate this pathway?”
The mechanism by which T cells are suppressed, she said, is tissue specific rather than oncogene specific. Mouse models of mammary adenocarcinoma, squamous cell carcinoma, and non–small cell lung adenocarcinoma have helped elaborate the importance of blocking the Th2 phenotype or promoting the Th1 pathway, resulting in CD8+ T cell mobilization. When the balance shifts to a Th1-predominant milieu, said Dr. Coussens, the host environment becomes angiostatic, immunostimulatory, and ultimately antitumorigenic.
In humans with chronic lymphocytic leukemia, the BTK pathway is activated in B cells and in the myeloid compartment. BTK inhibitors such as ibrutinib are currently in use for lymphomas and chronic lymphocytic leukemia.
Though BTK positive cells are also seen in pancreatic cancer. Dr. Coussens said that pancreatic cancer had been considered largely immunologically inert until recently, when researchers have begun to pay more attention to humoral immunity in the disease. However, asked Dr. Coussens, “Does the humorally mediated signature appear as a tractable target?”
To help answer the question, Dr. Coussens and her collaborators have recently shown that BTK inhibition improves response to gemcitabine in pancreatic cancer in a mouse model. Mice with an induced pancreatic tumor received the BTK inhibitor (BTKi) termed ACP-196 alone, gemcitabine alone, both, or neither. After 28 days, the combination group had significantly smaller tumor size than any other group.
Decreased desmoplasia was seen in tumor pathology when gemcitabine was combined with another BTKi, ibrutinib, said Dr. Coussens. An early dosing strategy, she said, shows that BTKi can also be effective as monotherapy when begun early enough in both tumor models studied.
Current clinical trials are underway investigating BTK inhibition in combination with conventional chemotherapy for pancreatic duct adenocarcinoma, as well as for head and neck squamous cell carcinoma.
Potential mechanisms for the promising efficacy of BTK inhibition in solid tumors include regulation of macrophage adhesion to the extracellular matrix, with suppressed adhesion to VCAM-1, and suppressed integrin activation. “Tumors are quite likely dying as a consequence of failure to adhere outside of the tumor environment,” said Dr. Coussens.
Dr. Coussens reported being on the advisory boards of Pharmacyclics Inc (the manufacturer of ibrutinib); AstraZeneca; Cellgene; and Five Prime. She receives research support from multiple pharmaceutical companies.
On Twitter @karioakes
NEW YORK – Inflammation is a hallmark of solid tumors, and chronic inflammation is a key regulator of T cell biology and therapeutic response in cancer. Bruton’s tyrosine kinase (BTK), a target in blood cancers for BTK inhibitors such as ibrutinib (Imbruvica), also poses a promising means to modulate humoral immunity and quiet a tumorigenic environment in solid tumors.
At the first International Cancer Immunotherapy Conference, Lisa Coussens, Ph.D., professor and chair of the department of cell, developmental, and cancer biology at Oregon Health Sciences University and associate director of basic research at Knight Cancer Institute, Portland (Ore.), provided a background and summarized how she and collaborators are working to limit B cell activity through inhibiting BTK.
BTK is an enzyme that plays a role both in B cell maturation and mast cell activation. Dr. Coussens, noting the importance of humoral immunity in many cancers, cited the work of Karin de Visser, Ph.D., among other researchers, who has found that circulating immune complexes can be angiogenic and tumorigenic.
In particular, the T helper-2 pathway (Th2), to a much greater extent than the Th1 pathway, can be proangiogenic, profibrotic, and immune suppressive. In cancer, when this pathway is unregulated, it “lets a tumor grow and be bad,” said Dr. Coussens.
Dr. Coussens said that Dr. de Visser’s work asks the key question: “If we depleted B cells, could we abate this pathway?”
The mechanism by which T cells are suppressed, she said, is tissue specific rather than oncogene specific. Mouse models of mammary adenocarcinoma, squamous cell carcinoma, and non–small cell lung adenocarcinoma have helped elaborate the importance of blocking the Th2 phenotype or promoting the Th1 pathway, resulting in CD8+ T cell mobilization. When the balance shifts to a Th1-predominant milieu, said Dr. Coussens, the host environment becomes angiostatic, immunostimulatory, and ultimately antitumorigenic.
In humans with chronic lymphocytic leukemia, the BTK pathway is activated in B cells and in the myeloid compartment. BTK inhibitors such as ibrutinib are currently in use for lymphomas and chronic lymphocytic leukemia.
Though BTK positive cells are also seen in pancreatic cancer. Dr. Coussens said that pancreatic cancer had been considered largely immunologically inert until recently, when researchers have begun to pay more attention to humoral immunity in the disease. However, asked Dr. Coussens, “Does the humorally mediated signature appear as a tractable target?”
To help answer the question, Dr. Coussens and her collaborators have recently shown that BTK inhibition improves response to gemcitabine in pancreatic cancer in a mouse model. Mice with an induced pancreatic tumor received the BTK inhibitor (BTKi) termed ACP-196 alone, gemcitabine alone, both, or neither. After 28 days, the combination group had significantly smaller tumor size than any other group.
Decreased desmoplasia was seen in tumor pathology when gemcitabine was combined with another BTKi, ibrutinib, said Dr. Coussens. An early dosing strategy, she said, shows that BTKi can also be effective as monotherapy when begun early enough in both tumor models studied.
Current clinical trials are underway investigating BTK inhibition in combination with conventional chemotherapy for pancreatic duct adenocarcinoma, as well as for head and neck squamous cell carcinoma.
Potential mechanisms for the promising efficacy of BTK inhibition in solid tumors include regulation of macrophage adhesion to the extracellular matrix, with suppressed adhesion to VCAM-1, and suppressed integrin activation. “Tumors are quite likely dying as a consequence of failure to adhere outside of the tumor environment,” said Dr. Coussens.
Dr. Coussens reported being on the advisory boards of Pharmacyclics Inc (the manufacturer of ibrutinib); AstraZeneca; Cellgene; and Five Prime. She receives research support from multiple pharmaceutical companies.
On Twitter @karioakes
EXPERT ANALYSIS FROM THE FIRST INTERNATIONAL CANCER IMMUNOTHERAPY CONFERENCE
Immunotherapy: Inject locally, treat globally?
NEW YORK – “Inject locally, treat globally” may become a new mantra for cancer immunotherapy. Dr. Ronald Levy, professor and chief of the department of oncology at Stanford (Calif.) University, discussed impressive and durable systemic results from local treatment of tumors, reviewing his group’s recent work and discussing ongoing early stage clinical trials.
In the hope of triggering an immune response that induces a systemic CD8 T-cell response, Dr. Levy and other investigators began experimenting with intralesional injections of immunotherapies, with and without adjunctive radiation or chemotherapy. The principle has been evaluated in a mouse model, in which up to 80% of mice receiving intratumoral immunotherapy were cured. Now, human trials are underway for solid tumors as well as lymphoma.
An early clinical trial involving 15 patients with recurrent low-grade B-cell lymphoma combined targeted low-dose radiation of a single tumor site with injection of CpG, immune-boosting snippets of DNA, into the same site. Looking for partial or complete regression, investigators saw promising results, though some patients who were responders didn’t see full effect until 24 weeks after injection (J Clin Oncol. 2010 Oct 1;28[28]:4324-32). The overall objective response rate was 27%, although 80% of patients (12 of 15) had stable disease or partial or complete response through a median follow-up of 33.7 months. Some individual patients had marked regression or disappearance of bulky tumors at distant sites.
CpG – motifs of cytosines and guanines – were strung together, said Dr. Levy, with a sulfur rather than a phosphate backbone to make them more stable for injection. These bits of DNA, which are present in both bacteria and vertebrates, are an agonist for toll-like receptor 9, activating B cells and dendritic cells, and then tumor-specific T-cells.
Dr. Levy and his collaborators used a two-tumor mouse model to track intralesional injection effectiveness for a variety of immunotherapies. Mice seeded with tumor cells bilaterally over the abdomen were injected with CpG and two other immune therapies at a single abdominal tumor site, and bilateral regression, if any, was tracked in comparison to systemic immunotherapy (J Clin Invest. 2013;123[6]:2447-63).
Though both treatment arms had good initial response, 70% of the systemically treated mice relapsed by 150 days after injection, compared with just 10% of those receiving intratumoral therapy (P = .002).
Of the 23 mice whose therapy consisted of intratumoral administration of CpG together with anti-CTLA4 and anti-OX40 antibodies (aCTLA4 and aOX40), 21 (91%) were alive 50 days after treatment. These mice fared better than did those receiving any other intratumoral treatment combination (P = .004, compared with CpG+aOX40; P = .03, compared with aCTLA4), suggesting a synergistic benefit to the triple combination.
Somewhat surprisingly, even murine models that also had tumor seeding into brain tissue saw marked reduction or even resolution of brain tumors, showing that the blood-brain barrier does not impede the effect within the CNS.
What didn’t work? PD-1 inhibitors were not particularly effective at provoking a systemic effect when injected into tumors. Peritumoral injection, though theoretically taking advantage of some aspects of the tumor microenvironment, also did not show global effect.
Based on the human CpG + radiation trials and the mouse experiments, the research group is proceeding with phase I and II clinical trials of CpG in combinations with aCTLA4 and aOX40. These, Dr. Levy said, were more likely to be available clinically, and human intratumoral T regulatory cells are known to express both CTLA4 and OX40.
All agents and combinations had an enhancing effect, said Dr. Levy. “We like this treatment and trial design,” he said, noting that everyone sees benefit at the local injection site, and some see global results.
Dr. Levy discussed multiple studies, and he disclosed receiving grant support from Pfizer, Dynavax, and Bristol-Myers Squibb. He also has served as a consultant to Five Prime, Kite, BeiGene, Innate Pharma, Bullet Biotech, and Immune Design.
NEW YORK – “Inject locally, treat globally” may become a new mantra for cancer immunotherapy. Dr. Ronald Levy, professor and chief of the department of oncology at Stanford (Calif.) University, discussed impressive and durable systemic results from local treatment of tumors, reviewing his group’s recent work and discussing ongoing early stage clinical trials.
In the hope of triggering an immune response that induces a systemic CD8 T-cell response, Dr. Levy and other investigators began experimenting with intralesional injections of immunotherapies, with and without adjunctive radiation or chemotherapy. The principle has been evaluated in a mouse model, in which up to 80% of mice receiving intratumoral immunotherapy were cured. Now, human trials are underway for solid tumors as well as lymphoma.
An early clinical trial involving 15 patients with recurrent low-grade B-cell lymphoma combined targeted low-dose radiation of a single tumor site with injection of CpG, immune-boosting snippets of DNA, into the same site. Looking for partial or complete regression, investigators saw promising results, though some patients who were responders didn’t see full effect until 24 weeks after injection (J Clin Oncol. 2010 Oct 1;28[28]:4324-32). The overall objective response rate was 27%, although 80% of patients (12 of 15) had stable disease or partial or complete response through a median follow-up of 33.7 months. Some individual patients had marked regression or disappearance of bulky tumors at distant sites.
CpG – motifs of cytosines and guanines – were strung together, said Dr. Levy, with a sulfur rather than a phosphate backbone to make them more stable for injection. These bits of DNA, which are present in both bacteria and vertebrates, are an agonist for toll-like receptor 9, activating B cells and dendritic cells, and then tumor-specific T-cells.
Dr. Levy and his collaborators used a two-tumor mouse model to track intralesional injection effectiveness for a variety of immunotherapies. Mice seeded with tumor cells bilaterally over the abdomen were injected with CpG and two other immune therapies at a single abdominal tumor site, and bilateral regression, if any, was tracked in comparison to systemic immunotherapy (J Clin Invest. 2013;123[6]:2447-63).
Though both treatment arms had good initial response, 70% of the systemically treated mice relapsed by 150 days after injection, compared with just 10% of those receiving intratumoral therapy (P = .002).
Of the 23 mice whose therapy consisted of intratumoral administration of CpG together with anti-CTLA4 and anti-OX40 antibodies (aCTLA4 and aOX40), 21 (91%) were alive 50 days after treatment. These mice fared better than did those receiving any other intratumoral treatment combination (P = .004, compared with CpG+aOX40; P = .03, compared with aCTLA4), suggesting a synergistic benefit to the triple combination.
Somewhat surprisingly, even murine models that also had tumor seeding into brain tissue saw marked reduction or even resolution of brain tumors, showing that the blood-brain barrier does not impede the effect within the CNS.
What didn’t work? PD-1 inhibitors were not particularly effective at provoking a systemic effect when injected into tumors. Peritumoral injection, though theoretically taking advantage of some aspects of the tumor microenvironment, also did not show global effect.
Based on the human CpG + radiation trials and the mouse experiments, the research group is proceeding with phase I and II clinical trials of CpG in combinations with aCTLA4 and aOX40. These, Dr. Levy said, were more likely to be available clinically, and human intratumoral T regulatory cells are known to express both CTLA4 and OX40.
All agents and combinations had an enhancing effect, said Dr. Levy. “We like this treatment and trial design,” he said, noting that everyone sees benefit at the local injection site, and some see global results.
Dr. Levy discussed multiple studies, and he disclosed receiving grant support from Pfizer, Dynavax, and Bristol-Myers Squibb. He also has served as a consultant to Five Prime, Kite, BeiGene, Innate Pharma, Bullet Biotech, and Immune Design.
NEW YORK – “Inject locally, treat globally” may become a new mantra for cancer immunotherapy. Dr. Ronald Levy, professor and chief of the department of oncology at Stanford (Calif.) University, discussed impressive and durable systemic results from local treatment of tumors, reviewing his group’s recent work and discussing ongoing early stage clinical trials.
In the hope of triggering an immune response that induces a systemic CD8 T-cell response, Dr. Levy and other investigators began experimenting with intralesional injections of immunotherapies, with and without adjunctive radiation or chemotherapy. The principle has been evaluated in a mouse model, in which up to 80% of mice receiving intratumoral immunotherapy were cured. Now, human trials are underway for solid tumors as well as lymphoma.
An early clinical trial involving 15 patients with recurrent low-grade B-cell lymphoma combined targeted low-dose radiation of a single tumor site with injection of CpG, immune-boosting snippets of DNA, into the same site. Looking for partial or complete regression, investigators saw promising results, though some patients who were responders didn’t see full effect until 24 weeks after injection (J Clin Oncol. 2010 Oct 1;28[28]:4324-32). The overall objective response rate was 27%, although 80% of patients (12 of 15) had stable disease or partial or complete response through a median follow-up of 33.7 months. Some individual patients had marked regression or disappearance of bulky tumors at distant sites.
CpG – motifs of cytosines and guanines – were strung together, said Dr. Levy, with a sulfur rather than a phosphate backbone to make them more stable for injection. These bits of DNA, which are present in both bacteria and vertebrates, are an agonist for toll-like receptor 9, activating B cells and dendritic cells, and then tumor-specific T-cells.
Dr. Levy and his collaborators used a two-tumor mouse model to track intralesional injection effectiveness for a variety of immunotherapies. Mice seeded with tumor cells bilaterally over the abdomen were injected with CpG and two other immune therapies at a single abdominal tumor site, and bilateral regression, if any, was tracked in comparison to systemic immunotherapy (J Clin Invest. 2013;123[6]:2447-63).
Though both treatment arms had good initial response, 70% of the systemically treated mice relapsed by 150 days after injection, compared with just 10% of those receiving intratumoral therapy (P = .002).
Of the 23 mice whose therapy consisted of intratumoral administration of CpG together with anti-CTLA4 and anti-OX40 antibodies (aCTLA4 and aOX40), 21 (91%) were alive 50 days after treatment. These mice fared better than did those receiving any other intratumoral treatment combination (P = .004, compared with CpG+aOX40; P = .03, compared with aCTLA4), suggesting a synergistic benefit to the triple combination.
Somewhat surprisingly, even murine models that also had tumor seeding into brain tissue saw marked reduction or even resolution of brain tumors, showing that the blood-brain barrier does not impede the effect within the CNS.
What didn’t work? PD-1 inhibitors were not particularly effective at provoking a systemic effect when injected into tumors. Peritumoral injection, though theoretically taking advantage of some aspects of the tumor microenvironment, also did not show global effect.
Based on the human CpG + radiation trials and the mouse experiments, the research group is proceeding with phase I and II clinical trials of CpG in combinations with aCTLA4 and aOX40. These, Dr. Levy said, were more likely to be available clinically, and human intratumoral T regulatory cells are known to express both CTLA4 and OX40.
All agents and combinations had an enhancing effect, said Dr. Levy. “We like this treatment and trial design,” he said, noting that everyone sees benefit at the local injection site, and some see global results.
Dr. Levy discussed multiple studies, and he disclosed receiving grant support from Pfizer, Dynavax, and Bristol-Myers Squibb. He also has served as a consultant to Five Prime, Kite, BeiGene, Innate Pharma, Bullet Biotech, and Immune Design.
EXPERT ANALYSIS FROM THE FIRST INTERNATIONAL CANCER IMMUNOTHERAPY CONFERENCE