Michael Davies, MD, discusses the biggest challenges in
treating brain metastases, what is known about the connection to the PI3K/AKT
pathway, and what his future plans are for research in this area.
If we could detect brain metastasis at an early stage, they
could potentially be cured with focal radiation approaches or surgical
approaches. For patients who have advanced disease with brain metastases,
hopefully an improved understanding of the molecular pathogenesis of these
tumors will lead to treatments that are not only rational, but more effective.
What are the next steps in your research?
There are many different ways to target the PI3K pathway, so
one of the biggest questions is, “Which of those targets are most likely to be
effective?” We are evaluating different strategies to target the pathway and,
importantly, we are evaluating different strategies in combination with other
therapies, including targeted therapy, immunotherapy, and radiation therapy.
We know that melanoma is a very complex disease, and the PI3K pathway is equally complex. It can be activated multiple different ways and it can have multiple different effectors. How it intersects with other oncogenic pathways that are clinically significant in this disease, remains an ongoing and important area of research.
We know that melanoma is a very complex disease, and the PI3K pathway is equally complex. It can be activated multiple different ways and it can have multiple different effectors. How it intersects with other oncogenic pathways that are clinically significant in this disease, remains an ongoing and important area of research.
Do you think that combination therapies will be key to successfully targeting the PI3K pathway?
Absolutely. What we generally see is that the PI3K pathway
does not drive tumor growth by itself, but it compliments other pathways to
make tumors much more aggressive and resistant to therapies.
Is a clinical trial investigating the use of PI3K in patients with melanoma who have brain metastases on the horizon?
The challenge with getting a clinical trial up and running is the hesitancy of pharmaceutical companies to include brain metastases in trials. This is something that is slowly changing, as we have now seen clinical trials with both BRAF inhibitors with ipilimumab and PD-1.However, often trials are done after most of the other clinical testing has been completed. It’s an active area of work for investigators in the field and for patient advocates to try and encourage companies to develop earlier stage clinical trials for patients with brain metastasis. This remains a critical unmet need for patients with this disease.
Weber
said acute toxicities that have been associated with TIL therapy
include hemorrhagic cystitis, cytoxan-induced syndrome of inappropriate
antidiuretic hormone, neutropenic fever/ sepsis, and
hypotension/capillary leak. He said researchers have adjusted to these
toxicities by limiting IL-2 to 6 doses after TIL infusion therapy.
Chronic toxicities have included fatigue, neuropathy, vitiligo, and
uveitis, Weber noted.
The process used to take 6 or more hours, multiple incubators, and multiple technicians. Today, he said, with the use of bioreactors and a closed system, the process is more efficient and only requires one technician. There is still more work to be done to make the process even better, he noted. The approach is moving forward in the phase II, multicenter LN-144 study, which aims to assess the safety, feasibility, and antitumor activity of this treatment followed by IL-2 for patients with metastatic melanoma who are refractory to at least one systemic therapy.3 Researchers are seeking to enroll 20 patients.
For trial inclusion, patients must have measurable disease with at least one lesion that is resectable for TIL generation; that is, at least 1.5 cm in diameter and able to be removed with minimal morbidity. Exclusion criteria include prior cell transfer therapy that included a nonmyeloablative or myeloablative chemotherapy regimen, more than three brain metastases, and current use of a systemic steroid regimen.
This trial is an exciting early step, according to Steven A. Fischkoff, MD, chief medical officer of Lion Biotechnologies, Inc, a New York City–based company that is developing the TIL therapy under an orphan drug designation. He said that focusing on TILs is a forward-looking approach to immunotherapy. Weber, who is a member of Lion’s scientific advisory board, said the technology holds promise for a variety of tumor types. Besides melanoma, other cancer types that might prove amenable to TIL therapy include renal cell carcinoma, ovarian cancer, glioblastoma multiforme, lung cancer, and cervical cancer, he said.
“You can definitely grow TILs from a variety of tumors,” Weber said. “In the old days, people tried to do it and couldn’t figure out what to do. It turns out to be much easier to do than we thought.”
- See more at: http://www.onclive.com/publications/oncology-live/2016/vol-17-no-7/tils-advancing-as-melanoma-immunotherapy-option/2#sthash.L6J2IajY.jORat1Jw.dpuf
Looking Forward
One key challenge in TIL therapy that has been partially overcome, Weber said, is finding a better way to grow TILs.The process used to take 6 or more hours, multiple incubators, and multiple technicians. Today, he said, with the use of bioreactors and a closed system, the process is more efficient and only requires one technician. There is still more work to be done to make the process even better, he noted. The approach is moving forward in the phase II, multicenter LN-144 study, which aims to assess the safety, feasibility, and antitumor activity of this treatment followed by IL-2 for patients with metastatic melanoma who are refractory to at least one systemic therapy.3 Researchers are seeking to enroll 20 patients.
For trial inclusion, patients must have measurable disease with at least one lesion that is resectable for TIL generation; that is, at least 1.5 cm in diameter and able to be removed with minimal morbidity. Exclusion criteria include prior cell transfer therapy that included a nonmyeloablative or myeloablative chemotherapy regimen, more than three brain metastases, and current use of a systemic steroid regimen.
This trial is an exciting early step, according to Steven A. Fischkoff, MD, chief medical officer of Lion Biotechnologies, Inc, a New York City–based company that is developing the TIL therapy under an orphan drug designation. He said that focusing on TILs is a forward-looking approach to immunotherapy. Weber, who is a member of Lion’s scientific advisory board, said the technology holds promise for a variety of tumor types. Besides melanoma, other cancer types that might prove amenable to TIL therapy include renal cell carcinoma, ovarian cancer, glioblastoma multiforme, lung cancer, and cervical cancer, he said.
“You can definitely grow TILs from a variety of tumors,” Weber said. “In the old days, people tried to do it and couldn’t figure out what to do. It turns out to be much easier to do than we thought.”
- See more at: http://www.onclive.com/publications/oncology-live/2016/vol-17-no-7/tils-advancing-as-melanoma-immunotherapy-option/2#sthash.L6J2IajY.jORat1Jw.dpuf
Interesting to think about. Here is a pic of the molecular pathways in melanoma.
Keep the thinking coming! -c
Keep the thinking coming! -c
Weber
said acute toxicities that have been associated with TIL therapy
include hemorrhagic cystitis, cytoxan-induced syndrome of inappropriate
antidiuretic hormone, neutropenic fever/ sepsis, and
hypotension/capillary leak. He said researchers have adjusted to these
toxicities by limiting IL-2 to 6 doses after TIL infusion therapy.
Chronic toxicities have included fatigue, neuropathy, vitiligo, and
uveitis, Weber noted.
The process used to take 6 or more hours, multiple incubators, and multiple technicians. Today, he said, with the use of bioreactors and a closed system, the process is more efficient and only requires one technician. There is still more work to be done to make the process even better, he noted. The approach is moving forward in the phase II, multicenter LN-144 study, which aims to assess the safety, feasibility, and antitumor activity of this treatment followed by IL-2 for patients with metastatic melanoma who are refractory to at least one systemic therapy.3 Researchers are seeking to enroll 20 patients.
For trial inclusion, patients must have measurable disease with at least one lesion that is resectable for TIL generation; that is, at least 1.5 cm in diameter and able to be removed with minimal morbidity. Exclusion criteria include prior cell transfer therapy that included a nonmyeloablative or myeloablative chemotherapy regimen, more than three brain metastases, and current use of a systemic steroid regimen.
This trial is an exciting early step, according to Steven A. Fischkoff, MD, chief medical officer of Lion Biotechnologies, Inc, a New York City–based company that is developing the TIL therapy under an orphan drug designation. He said that focusing on TILs is a forward-looking approach to immunotherapy. Weber, who is a member of Lion’s scientific advisory board, said the technology holds promise for a variety of tumor types. Besides melanoma, other cancer types that might prove amenable to TIL therapy include renal cell carcinoma, ovarian cancer, glioblastoma multiforme, lung cancer, and cervical cancer, he said.
“You can definitely grow TILs from a variety of tumors,” Weber said. “In the old days, people tried to do it and couldn’t figure out what to do. It turns out to be much easier to do than we thought.”
- See more at: http://www.onclive.com/publications/oncology-live/2016/vol-17-no-7/tils-advancing-as-melanoma-immunotherapy-option/2#sthash.L6J2IajY.jORat1Jw.dpuf
Looking Forward
One key challenge in TIL therapy that has been partially overcome, Weber said, is finding a better way to grow TILs.The process used to take 6 or more hours, multiple incubators, and multiple technicians. Today, he said, with the use of bioreactors and a closed system, the process is more efficient and only requires one technician. There is still more work to be done to make the process even better, he noted. The approach is moving forward in the phase II, multicenter LN-144 study, which aims to assess the safety, feasibility, and antitumor activity of this treatment followed by IL-2 for patients with metastatic melanoma who are refractory to at least one systemic therapy.3 Researchers are seeking to enroll 20 patients.
For trial inclusion, patients must have measurable disease with at least one lesion that is resectable for TIL generation; that is, at least 1.5 cm in diameter and able to be removed with minimal morbidity. Exclusion criteria include prior cell transfer therapy that included a nonmyeloablative or myeloablative chemotherapy regimen, more than three brain metastases, and current use of a systemic steroid regimen.
This trial is an exciting early step, according to Steven A. Fischkoff, MD, chief medical officer of Lion Biotechnologies, Inc, a New York City–based company that is developing the TIL therapy under an orphan drug designation. He said that focusing on TILs is a forward-looking approach to immunotherapy. Weber, who is a member of Lion’s scientific advisory board, said the technology holds promise for a variety of tumor types. Besides melanoma, other cancer types that might prove amenable to TIL therapy include renal cell carcinoma, ovarian cancer, glioblastoma multiforme, lung cancer, and cervical cancer, he said.
“You can definitely grow TILs from a variety of tumors,” Weber said. “In the old days, people tried to do it and couldn’t figure out what to do. It turns out to be much easier to do than we thought.”
- See more at: http://www.onclive.com/publications/oncology-live/2016/vol-17-no-7/tils-advancing-as-melanoma-immunotherapy-option/2#sthash.L6J2IajY.jORat1Jw.dpuf
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