The next paper has been awarded the Journal of Neuro-Oncology Award. The Journal of Neuro-Oncology is the official journal of the Section on Tumors of the AANS and the CNS for a paper entitled, Evaluation of Durable Response Rate in the Post-Resection Setting and Association with Survival in Patients with Recurrent High-Grade Glioma who Received Vosimogene Emiretroprevac and 5-Fluorocytosine Treatment, presented by Dr. Bob Carter and discussed by myself and Dr. Jim Marker. Congratulations, Dr. Carter. Thank you to the organizing committee for this opportunity to present on behalf of the co-authors and this recognition. I will be talking about the evaluation of durable response rate in patients treated with a novel retroviral vector therapy. I have participated in a consultative meeting designing a phase three trial of this therapy. This particular therapy is a therapy which involves a retroviral vector that encodes a pro-drug activating enzyme, cytosine deaminase. This enzyme converts an antifungal drug, 5-FC, to an anti-cancer drug, 5-FU. The therapy involves a strategy whereby the virus is administered to the tumor, and in this context it's allowed to propagate within the tumor for a period of time prior to the administration of the pro-drug, which then has a lytic effect on the tumor. The virus is able to propagate in cancer cells due to defects in the innate immune capacity of these cells, whereby in normal cells it does not propagate and is rapidly eliminated. In addition, this virus only integrates into dividing cells consistent with the cancer cells in the tumor microenvironment. So this combination therapy again involves the virus, which I will go by the trade name for a shortening effect, TOCA511, and the chemotherapeutic agent, the 5-FC. This is a schematic of how the strategy works, in particular in these patients who present with recurrence, the tumor is visible and then a resection is undertaken. The virus is injected into the resection cavity and allowed to propagate for a period of time. Because of the prior characteristics of the tumor microenvironment, which I mentioned, we see the expression of the cytosine deaminase gene in the tumor microenvironment, but it is not propagating in the normal cells or the normal brain tissue in these patients. As this propagation occurs and more and more tumor cells are infected, then the pro-drug activating component of the therapy is administered. So this is a step two. This is given orally as a prolonged release 5-FC, which is then converted intratumorally by the cytosine deaminase, which is now being expressed to 5-FU, a chemotherapeutic agent. In this context, there are now lysis of the tumor cells, but in addition, there is an active immune infiltrate of lymphocytes that causes an additional immune response, a combination of both lysis and immunotherapy. This combination is particularly powerful, activating durable anti-cancer immune response in preclinical models. For example, in control mice, which have no treatment, tumors rapidly grow and progress to kill the animal. In immune deficient animals, this therapy can also be given, but when it is given, there is actually a lytic effect of the tumor, but the tumor rapidly recurs, and this can be done actually cyclically in these mice. However, in an immune-competent mouse, when this particular therapeutic is given, the lysis of the tumor cells occurs, and the immune component is activated, and there is persistent abrogation of tumor growth. What we see also in these, quote, cured mice is that actually there is a component where they are able to resist the challenge of additional tumor cells into the opposing flank, and in fact, T-cells from these cured mice, when adoptively transferred now to naive mice that simply bear a tumor but have had no treatment administered, these adoptively transferred T-cells also cause abrogation of tumor growth, consistent with an immune mechanism of this particular therapeutic. So this is a cancer-selective immunotherapeutic that has two components. We believe that both the cancer cells, which are infected by the virus, and then lysed by the chemotherapeutic agent, activate certain danger signals and danger pathways, which, again, activate antigen-presenting cells, and this primes T-cells to infiltrate in both CD4 and CD8-positive cells. In addition, resident in the tumor microenvironment at baseline, there are immune-suppressive cells, immune-suppressive myeloid cells. The 5-FU that's created through this therapeutic locally delivers sufficient concentrations to kill off these cells. So both a natural immune-suppressive component of the microenvironment is abrogated, and in combination with the lysis, an immunotherapy is created. In this Phase 1 study, it's an ascending dose trial of safety and tolerability of the combination of the retroviral vector and the prolonged-release 5-FU, 5-FC. These were recurrent high-grade glioma patients, adult patients. Patients were required to be with a single contiguous tumor of less than 5 centimeters in diameter, with a planned greater than 80% resection of the tumor. They underwent surgery, and following surgery, they were administered the virus in escalating doses, anywhere from approximately 10 to the 7th infectious units to about 10 to the 9th infectious units. And then the cyclical TOCA 5-FC, or the 5-FC prolonged-release, was administered, again, in varying doses, ranging up to approximately 200 milligrams per kilogram per day. And then the primary outcomes to evaluate were safety, tolerability, and maximum tolerated dose. The basic demographics show that the patients enrolled overall in this trial in Phase 1 study were 56 patients. About 80% of these patients were glioblastoma patients, about 20% lower-grade tumors, grade 3. In addition, the average age was in the mid-50s, and the proximate number of recurrences for about half the patients was a first recurrence, and for about half the patients, it was a second or third recurrence. So these are patients that have already failed standard radiation chemotherapy, such as temozolomide. Notably, in the outcomes analysis of this particular cohort, all radiographic responders have progressed to a complete response, and they remain alive today. This group of responders, or the highest proportion of patients who have evidence of a radiographic response, occurred in the highest-dose cohort. That is to say, approximately 5 out of the 23 patients in the higher-dose cohorts of this particular therapy demonstrated this radiographic response. And this 20% compares favorably to historical controls, which are treated with chemotherapy. This is a swimlane chart, which shows the kinds of patients. Patients are receiving the therapy here at initial recurrence and resection, and then a variety of both radiographic responses and clinical responses are noted. These are the patients with the longest survival. Three of the patients were glioblastoma patients with a wild-type IDH, and two of the patients were anaplastic osteocytoma patients with a mutated IDH1 tumor. This is an example of a radiograph of one of the responding patients treated in 2014 with initial recurrence. This is after a resection about a year previously. The patient then, over a couple of months, has development of increased tumor size, undergoes a first resection, a recurrent resection, with a gross total resection, and administration of the virus. In the period prior to the administration of the chemotherapeutic agent, there's a slight increase in tumor size. But then, over a year later, there's stable disease. Finally, two years later, a partial response. And then three years later, no enhancing tumor visible. And a patient is alive with an ongoing complete response at greater than 36 months. Looking at the various associated toxicities with the viral therapy, which is the TOCA 511, this had a very low rate of treatment-related adverse events. Less than a handful of patients, 7%, that had greater than a grade 3 toxicity. And you can see these toxicities listed here. Similarly, the 5FC, which is the oral chemotherapeutic agent, which is given in cyclical fashion following the administration of the virus, was also well-tolerated with a low rate of higher-than-grade 3 toxicities. In conclusion, TOCA 511, in combination with an oral prodrug 5FC, activates in preclinical models a T-cell-mediated immune response. And this treatment was well-tolerated in patients with very few high-grade toxicities. This resection study also showed prolonged survival compared to historical benchmarks. And in a subset of the patients, 23 patients that received the highest doses, there were patients that had long-term durable responses. Obviously, this requires additional study at the level of a phase 3 clinical trial to understand whether or not this would be a benefit of the therapy versus some other characteristic of the patients themselves. But this phase 1 study has supported the development of a phase 3 trial. Schematically, I'll just show you that the plan is for approximately 380 patients to be enrolled, randomized to the therapeutic or to chemotherapy, and this is a multi-site trial. I'm thankful to the many investigators that are participating in this study. Thank you. APPLAUSE Thank you. I'll disclose an unusual conflict in that Dr. Carter is my boss. Carter and colleagues present a phase 1 trial of a novel malignant glioma treatment, a retroviral vector injected into surgical cavity walls after recurrent glioma resection, which later activates a systemically given prodrug. The goal of any phase 1 safety study is to find the best safe dose for later efficacy trials. This study, with limited serious observed toxicity, achieved its goal. A phase 1 trial can also suggest treatment benefit on occasion. Here, treated patients lived modestly longer than historical controls. With few treated patients, it is hard to gauge the strength of this evidence. Although some long-term survivors also had imaging responses, we can't claim this as additional evidence that the treatment works. This swim lane plot shows that imaging responses, circled in red, began nearly a year after the treatment, when most non-responders, the lower bars, had already died. An independent factor, like IDH mutation or robust intrinsic patient immune status, may explain both the response and the survival. Arguments explaining survival by response are generally avoided in the field of oncology. Could I get my slides, please? While they're working on getting the slides up, I'd like to congratulate Dr. Carter for the results of this significant study. Immunotherapy has been a game-changer in a variety of cancers, but not glioma, with many of our phase 3 trials of checkpoint inhibitors and even promising vaccine candidates not reaching their desired endpoints, as shown here. One potential explanation for this failure is that gliomas, with their low numbers of neoantigens, shown here, compared to other tumors, tumor-infiltrating lymphocytes, are immunologically cold tumors that cannot be expected to respond to immunotherapy. Viral therapy has been proposed as a means to turn immunologically cold tumors into hot tumors by changing the immune homeostasis within those tumors to favor an antitumor immune response. Some potential mechanisms for such a change are outlined here. 5.1.1 is a viral immunotherapy that's modified to produce its antiglioma response by changing the immunologic microenvironment to favor antitumor CD4 and CD8 responses, as shown in this diagram. This regimen resulted in an oppressive frequency of durable responses to treatment in this study, even at third recurrence. Interpretation of these studies, however, does require some caution, as the comparison group is not entirely comparable. Patients in the historical control could have had larger multifocal tumors and even unresectable tumors, and all tumors in that study were GBMs, and so that group might be expected to have a worse outcome, even at baseline. Nonetheless, five complete durable responses in this heavily pretreated group is impressive, and we look forward to the results of the ongoing Phase III study. Congratulations again to Dr. Carter and his colleagues for this important work. APPLAUSE

Dr. Bob Carter

Journal of Neuro-Oncology Award

High-Grade Glioma

Vosimogene Emiretroprevac

Phase 3 Trial