ONCS: Combination Cancer Immunotherapy—A Virtual Roundtable
Dec 26, 2014 19:44:55 GMT
lcd, RLC, and 1 more like this
Post by JHam on Dec 26, 2014 19:44:55 GMT
If you haven't read this article, it is definitely worth the read. It is a "virtual" roundtable discussion including Merck and Oncosec (Dr. Pierce). Pasting Pierce's discussion below:
www.lifescienceleader.com/doc/combination-cancer-immunotherapy-a-virtual-roundtable-0004
Why Combinations?
Our drug-development strategy is to combine our IL-12 treatment with anti-PD-1 or other checkpoint inhibitors because the two mechanisms seem to work together so well. There is a “monotherapeutic fetishism” in traditional oncology; many good drugs probably would be extremely safe and have synergistic activity when combined, but they never get through development because they don’t show monotherapy activity. Fortunately, intratumoral IL-12 electroporation has monotherapy activity. So, how do we augment the immunogenicity of tumors? We use intratumoral electroporation to deliver IL-12, which sits at the top of a hierarchy of cytokines, which drives immunogenicity and potent antitumor immunity. This is not just a local ablation. With the intratumoral injection of IL-12, we get systemic immune responses in more than half of the treated patients, and we are also getting a large TIL response — the key to boosting response to anti-PD-1.
Essential Components?
All the possible components will have to go through clinical trials. The entire clinical and regulatory community recognizes that the future will bring more combination immunotherapy trials. We need to figure out means to choose rational and safe combinations and make the process more practical. Even when you have squeaky-clean molecules, regulators understandably worry about synergistic toxicities. Anti-PD-1 has a really low toxicity profile compared to say, ipilimumab or IL-2, and with our IL-12, we haven’t had a single drug-related serious adverse event. But it’s fair to say, if you’re having synergistic efficacy, you may also have synergistic side effects.
Backbone Therapy?
PD-1 therapy is a straightforward story: If you look in a microscope and you see the PD-1+ TILs in the tumor nestled together with PD-L1+ tumor and macrophages, that patient will likely respond to an anti- PD-1 drug. That is a beautiful piece of biology, but the vast majority of patients do not respond to anti-PD-1 monotherapy. This is the biggest unmet medical need in immunotherapy.
Narrow or Wide Applications?
While I was at Merck, we developed an anti-PD-L1 antibody immunohistochemistry assay, and it became immediately clear that — across the board — there exists a subpopulation of patients in most all tumor types who have the PD-L1/PD-1+ TIL “adaptive resistance” phenotype, which we know predicts response to PD-1 or PD-L1 therapy. So, the potential benefit of checkpoint inhibition cuts across almost all cancers. We have to think of tumors in a new way. In looking at response to immune checkpoint therapy, the tumor’s tissue and cell of origin doesn’t seem to matter as much as the immunophenotype. In particular, this means the presence of the right TIL signature.
Personal or Broad?
It is not wrong to think of our IL-12 drug as in-situ vaccination. But unlike other vaccines, in delivering IL-12 into the tumor, we don’t have to rationally choose a specific antigen to suit the immune system in a particular patient. Some of the more forward-thinking vaccine technology engineers a synthetic consensus of multiple antigens. We solve the problem by killing tumor cells in situ, releasing all the potential antigens present in the tumor, and letting the immune system sort out what antigens are important for response.
Commercialization Challenges?
We are already in discussions about a combination of anti-PD-1 and our drug, and there are a lot of other immunotherapy companies thinking along the same lines. Novel-novel combos are particularly challenging from a regulatory perspective. We have already seen examples of enhanced toxicity with combinations of immunotherapies. And we certainly don’t have predictive models for these therapies. Intratumoral gene therapies like ours present a preclinical safety assessment challenge because the mouse tumor models are of such short duration, typically less than three to four weeks. As a community, we will have to work toward better solutions.
We have another unique challenge: IL-12 has been shown to convert myeloid-derived suppressor cells into real APCs (antigen-presenting cells). We are in effect (not actuality) converting a tumor into a lymph node, so we don’t want to kill off the tumor completely too fast. We need to apply just the right amount of IL-12, because we need the conversion to take place and leverage the local effects to drive a systemic antitumor response.
www.lifescienceleader.com/doc/combination-cancer-immunotherapy-a-virtual-roundtable-0004
Why Combinations?
Our drug-development strategy is to combine our IL-12 treatment with anti-PD-1 or other checkpoint inhibitors because the two mechanisms seem to work together so well. There is a “monotherapeutic fetishism” in traditional oncology; many good drugs probably would be extremely safe and have synergistic activity when combined, but they never get through development because they don’t show monotherapy activity. Fortunately, intratumoral IL-12 electroporation has monotherapy activity. So, how do we augment the immunogenicity of tumors? We use intratumoral electroporation to deliver IL-12, which sits at the top of a hierarchy of cytokines, which drives immunogenicity and potent antitumor immunity. This is not just a local ablation. With the intratumoral injection of IL-12, we get systemic immune responses in more than half of the treated patients, and we are also getting a large TIL response — the key to boosting response to anti-PD-1.
Essential Components?
All the possible components will have to go through clinical trials. The entire clinical and regulatory community recognizes that the future will bring more combination immunotherapy trials. We need to figure out means to choose rational and safe combinations and make the process more practical. Even when you have squeaky-clean molecules, regulators understandably worry about synergistic toxicities. Anti-PD-1 has a really low toxicity profile compared to say, ipilimumab or IL-2, and with our IL-12, we haven’t had a single drug-related serious adverse event. But it’s fair to say, if you’re having synergistic efficacy, you may also have synergistic side effects.
Backbone Therapy?
PD-1 therapy is a straightforward story: If you look in a microscope and you see the PD-1+ TILs in the tumor nestled together with PD-L1+ tumor and macrophages, that patient will likely respond to an anti- PD-1 drug. That is a beautiful piece of biology, but the vast majority of patients do not respond to anti-PD-1 monotherapy. This is the biggest unmet medical need in immunotherapy.
Narrow or Wide Applications?
While I was at Merck, we developed an anti-PD-L1 antibody immunohistochemistry assay, and it became immediately clear that — across the board — there exists a subpopulation of patients in most all tumor types who have the PD-L1/PD-1+ TIL “adaptive resistance” phenotype, which we know predicts response to PD-1 or PD-L1 therapy. So, the potential benefit of checkpoint inhibition cuts across almost all cancers. We have to think of tumors in a new way. In looking at response to immune checkpoint therapy, the tumor’s tissue and cell of origin doesn’t seem to matter as much as the immunophenotype. In particular, this means the presence of the right TIL signature.
Personal or Broad?
It is not wrong to think of our IL-12 drug as in-situ vaccination. But unlike other vaccines, in delivering IL-12 into the tumor, we don’t have to rationally choose a specific antigen to suit the immune system in a particular patient. Some of the more forward-thinking vaccine technology engineers a synthetic consensus of multiple antigens. We solve the problem by killing tumor cells in situ, releasing all the potential antigens present in the tumor, and letting the immune system sort out what antigens are important for response.
Commercialization Challenges?
We are already in discussions about a combination of anti-PD-1 and our drug, and there are a lot of other immunotherapy companies thinking along the same lines. Novel-novel combos are particularly challenging from a regulatory perspective. We have already seen examples of enhanced toxicity with combinations of immunotherapies. And we certainly don’t have predictive models for these therapies. Intratumoral gene therapies like ours present a preclinical safety assessment challenge because the mouse tumor models are of such short duration, typically less than three to four weeks. As a community, we will have to work toward better solutions.
We have another unique challenge: IL-12 has been shown to convert myeloid-derived suppressor cells into real APCs (antigen-presenting cells). We are in effect (not actuality) converting a tumor into a lymph node, so we don’t want to kill off the tumor completely too fast. We need to apply just the right amount of IL-12, because we need the conversion to take place and leverage the local effects to drive a systemic antitumor response.
