Dr. Merrick Ross outlines the expanding role of oncolytic immunotherapy in the treatment of melanoma.
Well welcome back everybody. Uh we will continue with the program. And our next speaker is once again Merrick Ross. Uh and Merrick one take it away. Mhm. Okay. Thanks very much terry and um thank you. Thank you Hugh again for the invitation. And everyone who worked so hard to put this virtual event together. So I thank you for that. And You only have to deal with my passion for 20 more minutes today. So um this is another area of uh a very important clinical in clinical research interest of mine that was initially called an intra regional therapy. And that now has been evolved into what we call an caloric immunotherapy. And we'll discuss issues related to its role in advanced stage melanoma. Oops. And there's my disclosures haven't changed since yesterday. So Okay, so this has been an interesting kind of journey. There is a long history of using the traditional or intradermal injections in treating a variety of cancers over over the years. And from a historical perspective there never really caught a lot of interest because there these are really based on anecdotal reports are really case series. But over the last five or 10 years there has been some novel agents that have emerged that have not not just locally a blade of activity of what we call on catalytic activity but also have elicited responses at distant un injected um tumor sites of what has been termed an episcopal effect. And these agents have been studied kind of like in parallel with the identification of uh the immune check playing blocking agents as well as targeted therapies that are for advanced melanoma. These distant responses that we've had that we have observed in patients getting local therapy are believed to be immulogic in nature. Because when you inject us with these agents, they are causing inflammatory cell death at the local site that elicits dangerous signals an exposure of specific emergence. And this leads to identified circulating levels of cd eight T cells. These are killer T cells in Yemen interfering and also induction of T cell infiltration into injected tumors as well as in un injected tumors as well. Because of these observations that have been very prospective, important phase one through three trials. And now it has been incorporated into the mainstream of melanoma treatment and melanoma clinical research and evolved into what we call our catalytic immunotherapy. So the goals of oncological immunotherapy is a locally innovative therapy for local disease control with high local concentration with minimal toxicity with into the local to us. The other goal is an induction of a systemic host immune anti tumor activity elicited, we think by a response that um at the local site but we see responses at un injected distant and regional metastases because there's some potential synergism with immune checkpoint blocking agents. These have really really been a major clinical research kind of kind of focus. But the synergism is also resulting in only very minimal additional toxicity. And then the last goal is to overcome patients that we see. They have PD one resistance. So a lot of this is based on what's called the cancer immunity cycle. Which is really mostly a hypothesis that the immulogic activity with injecting agents into local to our cause is moral ISIS and release of derived antigens that are picked up by antigen presenting cells or apcs particularly dendritic cells which leads to T cell priming and T cell activation and generation of memory T cells that circulate throughout the body and then infiltrate into tumor. Then there's uh t. So it's a recognition of tumor cells and then destruction of the tumor cells by the T cells that are just kind of amplifies the cycle. And the interesting thing about this cancer immunity cycle is that you can see potential synergism with the analytic therapies and and the immune checkpoint blocking agents particularly anti C. T. L. A. For our hip illuminated we think works best at step two in terms of uptake process and presentation of tumor of tumor antigens within the antigen presenting cells and then anti PD one that seems to work at step six and seven where there is an enhanced he's a recognition and then killing of the um uh um ourselves by releasing the response of the immune system against the against the U. S. So you can see there's potential synergy between the analytic therapies and the immune checkpoint blocking agents. So these are the different categories that are under active clinical investigation. So these are the intra regional agents that have been in development for melanoma. We have the plasma D. N. A. Is toll like receptor agonists, some cytokines you know you know modular agents, inflammatory or dies or chemical objective. And then lastly but most important are the analytic viruses and actually tell imagine mama Perfect TyveK is currently the only agent here that is currently approved by the FDA for the use of advanced under a sectoral melanoma. They all have different mechanisms of action but they all seem to have some ability to elicit distant responses And un injected sites. So these are the patients that are really the best candidates for these therapies. And these patients have advanced stage disease. But I have accessible sites of injection. So specifically the patients within Transit disease. So these are the regionally metastatic disease that are under assessable. So these are the stage three B and three C. Without and with nodal metastases. You can inject a lift notes as well and pretty much anywhere in the body, the extremity trunk or had a neck region, distant skin and soft tissue. So the stage four in one AIDS. And then we have a smaller group of patients that have advanced disease at un injected sites might have other sites that are easily injectable. So let's talk about the different clinical setting trial settings that the acted like a clearly given your therapy has been studied and we'll start with mono therapy. So single agent. So this is t back to imagine how perfect it's a herpes simplex type one virus that's been genetically modified the two major modifications in part replication of the virus only within tumor cells. And the second modification um is an insertion of a gene that when the virus replicates and destroys the cell, the virus makes GM CSF. And the local administration of GM CSF seems to enhance the cytokine response at the local um injection site and that seems to be the most important mechanism of action that can elicit a physiologic response at distant sites. And this was studied in what's called the optimum trial which is the on Quebec's pivotal trial in melanoma Before it was Tv exit before I was Tyvek it was it was on Quebec's and this is a phase three randomized trial for unfair injectable but un respectable Stage three B and stage four melanoma where patients were randomized to the T. V. Neck injections versus injections of GM CSF. So you're gonna ask why what what kind of weird uh control arm is that? We understand that this trial was initiated prior to the approval of the main stage for agents that we have like targeted therapy or the immune checkpoint blocking agents. But since uh TyVEK makes GM CSF at the local site. It seemed reasonable to use GM CSF GM CSF injections as a as a control arm especially since there was some previous data showing that patients who received systemic injections of GM CSF, that there was some response in patients with Stage four disease. So that was the rationale for the control arm and this is the this is the design. Um It was a completed trial in about four years. Uh the the the primary implant was an interesting endpoint was durable response rate lasting for more than six months. And if you compare GM CSF to TyVEK, you can clearly see an improved response rate uh using the the the primary endpoint. And if we look at response rate overall 26% for patients receiving Tyvek and only 5% for patients who received GM CSF. So both of these endpoints were met and was really an important observation. It's also important to recognize that In the patients that had a response, 41% of those patients had a complete clinical response. So if we look at local injected responses versus non injected responses of in distant non injected responses, you can this is the waterfall plot for there's at least a 50% clinical response, 64% at lesions that were injected, 34% in non injected sites and then 18% at distant sites. So these are patients having at least a 50% response of many complete responders in the bystander or the non injected lesions. And here's a clinical example of a patient. We had multiple injections of TYVEK for under a sectoral disease, the circles of the target lesions and you can see that there is a complete clinical response or there's a lot of tumor here that responded that actually wasn't injected. And here's another example. The green arrows are the sites of injection. This is subcutaneous metastases. This is this nodal disease in the neck and these are these are un injected sites here. A distant distant disease. And you can see that all these sites responded with the only two sites that were injected where the neck and the subcutaneous area here. But all these other sites also responded as well. So this is the overall survival a nearer kind of overall survival improvement. Uh Not not quite um uh statistically significant. But if you look at stratified subsets the stage 33 B. And C. And stage four M. One A. Versus the patients. And it's more advanced disease. Whatever benefit was seen through the entire trial seemed to be benefited mostly in these patients here. And this was uh statistically uh improvement. An outcome compared to the control arm and based on this data as well as meeting the primary endpoint in october of 2000 and 15 T. That was approved in the US and approved in the U. S. A. And approved in the eastern eastern eastern european. I'm sorry the european union equivalent of the FDA in the U. S. Was approved a couple months later. And the interesting thing is that if you look at the subset analysis of the stage three B. And C. And stage four M. One A. Looking at universite and Multivariate analysis in terms of visceral metastases free survival. The patients who received the vet injections Had a significant reduction in development of visceral metastases. So there must be something going on systemically that prevents um distant disease failure. So 59% lower risk of developing visceral and bony metastases. And the patients that received T back. This is another arkalyk virus coxsackie virus 88 21 different mechanism of action and enters the cell by expression of something called Icam one and melanoma cells express icam one but the same concept. Once the virus enters to sell to sell the tumor cells get a bladed and a similar cascade of events happen. And we can see both local and distant responses with this this virus as well. And this is a phase a phase two trial for the three C. And stage four patients. And you can see a very nice kind of overall response rate that includes both local responses as well as distant responses. So another example of an apocalyptic virus resulting in some very nice responses. This is PV. 10 which is a chemical in a blade of um uh substance as a small molecule of forcing derivative. And it's a very nice preclinical models showing that the distant responses definitely are ideological in nature. And so how this works is that you inject the PV tending to the tumor cells. The set up the tumor cells. The pd time is taken up by the license zones within the tumor cells. The license um is then released their elliptic enzymes and actually because self destruction of the tumor cells but inflammatory sense. So you also get by standard responses as well. This is a phase two trial showing nice waterfall plots with very nice response rates in both local in distant sites. This is an A. T patient trial that we participated in. And then if you look at complete response plus partial response, it's 49% and the target lesions and 37% in non injected by standard lesions. And the other thing that was interesting that you had to have a significant local response to get a bystander response, which kind of makes sense. So again, if you look at bystander response of complete and partial That for patients who had a nice local response, there was a 67% um bystander response. But if there was minimal to no local response, you almost never saw a distant response again, suggesting that these distant responses are related to some sort of immunological mechanism. So let's talk about combinatorial uh combinatorial strategies with immune checkpoint blocking agent. So this is where a lot of the excitement is there's theoretical synergism and activity, little increase in toxicity. It's an attractive prospect for neo adjuvant approaches for respectable advanced regional disease and also as a potential option after failure of standard uh immune checkpoint blocking um uh Maino therapy either as a second line strategy for the purpose of overcoming PDF one resistance. So the the different compensatory directions that have been studied is T. Vac classical. Um Ahmad and a phase one B to trial that this has been already been published HF 10 which is another herpes simplex on politic virus principle. Um Ahmad and a similar design as a T Vac trial. Um And this cruel is completed and results are available. The most important trial is T Vac plus paperless A man versus embolism abalone is a randomized phase three registration trial and this is recently completed. And then there's an interesting PV 10 plus paperless amid as a phase two trial as well. If you look at um great great of toxic grade of toxicity of the different combinations and response rates that we've seen in under a sectoral stage three and stage four melanoma. Obviously the pan evo combinations have the highest response rate but also very high high toxicity as well. T that plus if um Ahmad has a 39% response rate. Uh HF 10 plus city lima mob almost 50% and the highest responders so far that we see is TyveK plus paperless a mob in the phase one B portion of the of this trial here which had a phase one B followed by a phase three. So this is the randomized trial of Tyvek plus paperless, A mob versus 80 vac, placebo injection plus Pemberley Samad. And this trial is being completed but we don't have the results yet. But the results of this trial is the most important will be the most important finding as to what the future of analytic therapy will be in combination with immune checkpoint blockade. Let's talk about a few comments about a neo adjuvant approach, the Russian and the rationale and clinical trial experience. So there's really only one mono therapy neo adjuvant trial with a narcoleptic and that's T VAC. And this is a stratified stage three B through stage four in one A. And those paces from the optimum trial were not that they had respectable disease were chosen to be candidates for the phase two trial of a randomized trial of interregional T Vac followed by surgery versus upfront surgery followed by whatever achievements were available. Unfortunately during this time period the FDA had not yet approved very effective adjuvant therapy like targeted therapy or immune checkpoint black engages. But interestingly enough um Based on the results from the optimal child that I showed you a 59% lower risk of distant disease. That was the reason why this group has chosen for a neo adjuvant approach. So here's the trial, phase two randomized trial of stage stage three B two, stage four M one A 12 weeks of TyveK injections followed by surgery versus upfront surgery at 21% complete pathologic response rate interesting. Not as high as some of the other neo agreement. So we talked about yesterday but improved relapse free survival of two years. It's pretty interesting. And now there's ongoing trials of analytics plus the mean checkpoint blocking agents in the neo edge of in space as well. So this is the single mono therapy uh neo edge of in trial of TyVEK and you can see the upfront surgery followed by some sort of achievement versus upfront TyVEK and then surgical resection And improve this is mine. Oh therapy. So it looks like the injection of TV for 12 weeks elicited something distantly to prevent distant failure because we've got to improve relapse free survival in the patients receiving T. Vac And improved two year overall survival so far. So it's pretty pretty interesting. And there's some clinical translational correlates. We see increased CD eight cell density development within the US that are injected with tyvek and the patients that had responses. So these are the patients in terms of relapse free survival that had increased CD A density and in the overall survival. So this actually correlates with an improved outcomes. So the last topic is Pd one overcoming Pd one resistance. And the rationale is that we have observed synergy of analytic therapy and immune checkpoint blocking agents and frontline settings and advanced stage three and stage four patients. And we see induction of T cell infiltrates into injected tumors, turning code tumors into hot tumors. So the concept is that if patients have failed mono therapy with with immune checkpoint blocking agents, we can hopefully change that response rate by injecting different agents into the tumor. So there's a variety of different Phase two trials that have looked at this that that will be studied further one in particular that Caroline agonist Principal umum adversity aluminium alone. So this was a randomized phase two second line in patients who failed anti PD one. And this randomized trial was based on a 30% response rate in combination in a previous phase two trial or since plasma dial 12 electoral operation plus paperless um and PV templates paperless um ab coxsackie virus plus a aluminum ab and then a phase one beach trial of another accolade called CMP. Um there's +001 plus anti pD one. So they continue the anti pd the immune checkpoint blocking agents and then add an injectable to see if you can get a response. So this is my last slide. So in terms of clinical practice scenarios we have on label use mono therapy for in transit disease patients with distant skin and soft tissue disease and nodal metastases. You can identify some patients that are have these injectable sites and have low volume visceral disease, if they have significant comorbidities where they may be are not able to tolerate immune checkpoint blocking agents. And that off label use would be right now there's no on label use for a combination with immune checkpoint black engagements because a lot of interest in trying to do this off label, but insurance companies are pretty much not very willing to do this. Um, certainly there are several clinical trials that are available that combine immune checkpoint blocking agents with the injectables. And I'll stop there and thank you for your kind attention. Thank you Merrick. And again, we will forward the questions to you so that can be answered and delivered to the attendees. Appreciate all your work on the course and we'll see you again next year. Thank you very much.
