The lack of efficacy for additional survival time in the DTIC control arm patients to the addition of YERVOY if available during the trial for the 130 control arm participants is extremely important.
To reiterate, DTIC is a DNA alkalating agent and an IMMUNE SUPPRESSOR. Since YERVOY is a monoclonal antibody and binds to CTLA-4 sites on CD-8 killer T cells, Yervoy's efficacy is inhibited by the fact that T cells are reduced and impaired for activation after DTIC therapy.
YERVOY theoretically will have a beneficial survivor effect on partial or nonresponders in the A-7 arm who have an intact immune system with CD-8 T cells that are not reduced or compromised and can be activated by YERVOY as you noted today ( VICL mouse model showed synergy between A-7 and YERVOY ). This fact will be very beneficial in adding survival time to the 260 A-7 arm participants if it was available to them.
IMO the data after this March sweep will show that the median overall survival of the A-7 arm is 10 months better than the DTIC control arm.
Sentiment: Strong Buy
The median survival from Newlink is 29 months from a group of much sicker patients (mostly second line without exclusion). The patients in Vical trial should have a median of at least 30 months without any treatment. By the way I do not believe in Newlink either.
If combine Allovectin-7 with Yervoy or anti-PD1, it might work better. However, that's beyond Vical's ability.
The NLNK is interesting maybe even promising but it has no relevance to expectations or forecasts for the allovectin trial. The NLNK study: 1. Was done at only one site. 2. Results were only 21 patients. 3. Although median OS was 29 months there was a sharp drop off in survival in the next couple of months. 4. Most important, half of the patients had all their tumors resected and were NED with just a risk of recurrance which is a whole different ball game in terms of survival expectations.
NLNK - Phase 2 Melanoma study -
Twenty-one of 25 patients completed the trial, with four stopping due to progressive disease. HyperAcute Melanoma was well tolerated without significant grade 3 or 4 toxicities associated with the vaccine. By RECIST criteria, of 16 stage IV patients there were two complete responders (CR), two with stable disease and three with no evidence of disease (NED) after resection. Among stage III patients, 3/9 remain disease free and one patient with slowly progressive disease remained alive for more than 30 months. The median overall survival in the study was 29 months, with 50% of the patients surviving for two years and 12/25 (48%) still alive. The anti-alpha-Gal antibody values increased after vaccination in 24/25 patients by up to 100-fold. All evaluable patients seroconverted, developing asymptomatic autoimmune antibodies. Anti-tyrosinase antibodies developed in seven of 23 patients correlating with one CR and one patient NED. Vitiligo developed in 4/25 patients, correlating with two complete responses and two patients stable continuing with no evidence of disease.
Sentiment: Strong Buy
Small clarification: I own VICL shares.
Second, the likely reason for the observed synergy between A-7 and Yervoy is that Yervoy makes T cells more reactive to antigen. CTLA-4 can be seen as a break on the wheel, and Yervoy releases that break. A-7 increases the rate of cross-presentation of TAAs to T cells, these two drugs should work hand in glove together. DTIC doesn't suppress the immune system, it rather destroys it. Immunosuppression means something else, such as the action of TRegs or MDSC's and their secreted anti-inlfammatory cytokines, prostaglandins, arginase and IDO.
Virtually all survivors in any study group represent the same class, look up Mark Smyth's work on this. This is probably true for patients who survive on DTIC vs Yervoy. So, if you look at the margin of the survivors in the Yervoy PIII, you get a few percent extra survivors, there are many patients in the Yervoy arm that would have been in the same place without risking death by taking it. Even if there are T cells present in a patient, most tumors have engineered an immunosupressive regime that makes the T cells deaf to the pleading of antigen presenting cells. This is the true nature of cancer, not a bunch of invincible cells that invade the body, but a bunch of weak cells full of mutations whose only hope of survival is to lull the immune system to sleep, they do this through intrinsic and extrinsic means. If the immune system ever wakes up to what is going on, you get spontaneous remission. The reason I own stock is that A-7 attacks the intrinsic immunoediting strategy of melanoma. Yervoy attacks the extrinsic part, but not very well.
Yervoy also kills a percentage of all who take it, There are likely people from the DTIC arm who would have been alive today, except they were given Yervoy. It is a nasty way to die too, your immune system mercilessly attacks your GI track. A-7 sounds better on all grounds, better to try pairing it with rIL-2 IMO.
"Yervoy makes T cells more reactive to antigen. CTLA-4 can be seen as a break on the wheel, and Yervoy releases that break. A-7 increases the rate of cross-presentation of TAAs to T cells, these two drugs should work hand in glove together. DTIC doesn't suppress the immune system, it rather destroys it."
It has recently come to my attention by way of a publication from BMS that this may not be true. It appears that Yervoy's therapeutic action may be through mediating ADCC against TRegs within the tumor. It's side effects are likely the result of CTLA-4 blockaid leading to increased, unregulated responses by T cells against self antigens. As metronomic paclitaxel also selectively kills TRegs, this may be a better agent to combine with A-7, fewer side effects, and it would be far cheaper. I wonder if the company has explored this...low does metronomic cyclophosphamide also has this effect, albeit temporarily, but should be long enough in the case of A-7.
Agree. Control arm median OS 15 months and A7 median OS 25 months is the most likely scenario. Other possible realistic outcome ranges are control arm median OS 13-14 months and A7 median OS 26months or control arm median OS 16-17 months and A7 median OS 24 months.