Hi Toad I have a macro in excel (easy to use) that generates KP curves using estimated time in trial and censored data. Send me an email (nhyujm6 at hotmail) and I will send you a blank version. Regards
Teg, ESPAC was a European trial. In Europe the selection criteria for resection is much more tighter than in the U.S. Thus, in Europe generally healthier patients with a better prognosis are surgically resected. This is evidenced in the difference in SOC values for the ESSPAC and RTOG trials. You should also note that the pronostic factors for IMPRESS patients are very very close to RTOG, not ESPAC, patients.
We also know that in recent history, relative to checkpoint inhibitors, cancer vaccines have become the "ugly cousin" of cancer immunotherapy. Immunotherapy of cancer must do more than simply present antigens to the immune system. Immune tolerance, which is active, acquired and dominant must be disrupted. This has led many who view the field from afar that the outlook for cancer vaccines is poor.
What is not appreciated by the generalists is that Hyperacute also promotes the innate immune function, which disrupts immune tolerance. For example, the majority of patients tested after Hyperacute vaccination have elevated levels of IL-5, which have a cooperative relationship with eosinophils. Eosinophils produced via this signalling pathway are implicated with tumor surveillance and clearance.
I think the market is in for an earthquake-scale shock when it learns that the existing one-size fits all view of cancer vaccines is incorrect.
Hopefully not long to wait!
Be, at 222 events the separation could have been there but there were too many censored patients to prove it statistically. What makes me lean towards this is I cannot model a scenario where 222 events occurs at Feb 2014 and there wasn't curve separation.
It simply relates to the amount of time all patients have been in trial to achieve a statistically significant result. The DMC dont have to wait to 333. They have the best interests of the patients at heart. They alluded to this at the investor meeting also. Caution: I could be wrong.
In this paper, researchers compared the infiltration of eosinophils and macrophages in small cell
esophageal carcinoma with patient survival. Kaplan-Meier analysis revealed that both the high macrophage infiltration group (p = 0.004) and high eosinophil infiltration group (p = 0.027) had significantly enhanced survival. See my twitter account (nhyujm6nhyujm6) for a photo. Notice how patients with high infiltration of eosinophils and macrophages demonstrated an initial survival benefit, similar to what was seen in the 300M cell group of the Ph 2 trial (1 year survival = 96%). Notably, a prolonged benefit was also seen in some patients.
The hyperacute vaccine is known to produce antibodies and antibody production is known to correlate with survival. However in the phase II trial, the pattern of Ab response was similar in both 100M and 300M dose cohorts. This implies that a second, separate mechanism is responsible for the dose-dependent nature of the Hyperacute vaccine. Eosinophils and macrophages, produced in a dose-dependent manner is likely to contribute to both an initial and prolonged survival benefit.
Many vaccine immunotherapies have failed because of tumor induced tolerance. Simply presenting antigens and a strong adjuvant to the immune system is not enough to disrupt the existing state of tolerance in the tumor environment.
It is my opinion only, but I believe the the majority of commentators out there are bearish on Hyperacute vaccine is because they incorrectly assume the same MOA as other vaccine therapies that have either failed or showed marginal benefit in subgroup analysis.
If you care to look under the bonnet of the phase II PC trial you can see evidence for a separate initial mechanism that could be related to tolerance removal (checkpoint inhibtion). Evidence for this is supported by the 1 year survival of the 300M cell group of 96%.
Standard immunotherapy vaccines typically show a benefit towards the tail of the KP curve, as acquired immune memory is utilized to prolong survival. However, initial survival benefits are typically associated with checkpoint inhibitors, rather the vaccines.
Hyperacute is different from other vaccine therapies because Neutrophils are produced. The neutrophils, particulary eosinophils are implicated in tumor macro environment clearing and tumor cell signalling changes, such as CALR expression. In contrast to memory B cells, this effect appears to be immediate and is also likely to be dose dependent.
Thus with Hyperacute, there are at least 2 mechanisms (maybe more) at play in the same treatment.
In addition, 222 events were reached in February 2014. This date could not have been reached if the SOC and treatment arm curves were the same up to 20 months (only to divererge after 20 months) - This type of scenario would have led to 222 events in July 2013. There must have been an initial offset, similar to what was seen in the PhII 300M subgroup for 222 events to occur as late as February 2014.
The above is my opinion based on my analysis and discussions with others. Although I think I'm right, I could be wro
There is also increasing evidence that prolonged repeated vaccine immuno-chemotherapy induces long-term clinical responses and survival - possibly via successive immunomodulation
Just to follow-up - there is also a market on tumor cells - CD27 - that is a "dont eat me" signal - which can potentially nullify the Calreticulin signal. Interestingly, Macrophages, such as Eosiniphils are known to disable CD27.
I would actually see July/August as the key milestone dates. This is the point where all patients have been in trial for long enough to stop for efficacy if the required hurdle has been met.
At ASCO NLNK will present data relating to patients which express Calreticulin. Calreticulin is a key "eat me" signal found on the surface of tumor cells. Patients that don't express Calreticulin on the tumor cell surface dont have a good prognosis because Calreticulin exposure dictates the immunogenicity of cancer cell death. If the patient expresses Calreticulin, then Hyperacute can produce Calreticulin Antibodies (Ab), resulting in cell death.
What is intriguing is that some chemotherapeutic agents and gamma-irradiation have been shown to induce ER stress and promote Calreticulin surface translocation in cancer cells, resulting in their recognition and phagocytosis by innate immune cells, such as macrophages and dendritic cells (DC). This is one possible mechanism for the chemosensitization effect: The Hyperacute injection primes the immune system, and even if the tumor cells dont initially express Calreticulin, they chemotherapy/radiation can promote Calreticulin surface expression, resulting in rapid cell death because the immune system has been primed by the Hyperacute injection.
This shows the intriguing relationship between chemotherapy and Hyperacute.
Indoxomid is already in the clinic in combination with (1) Docetaxel (PhII, BC) , a $3 billion/year Sanofi drug (2) Ipilimumab (PhI, melanoma), BMY (3) Temozolomide (PhI, gliobastoma), Merck (4) Nab-Paclitaxel (Abraxane), Gemcitabine (PhI, metastatic PC), Celgene & Eli Lilly.
If you are looking for a pretty PR that highlights these combinations, this is not the company for you.
Deep rivers run quiet.
). Results: The study reached its endpoint at 1 year with DFS of 62% and OS of 86%. Thirty-one of 64 patients (48%) had increased anti-CALR Ab. Patients responding with an increase in anti-CALR Ab had a median OS of 35.8 months compared to 19.2 months for patients without an increase. The positive correlation between increased anti-CALR Ab and improved median OS was statistically significant (p=0.03).Conclusions: This study of algenpantucel-L with SOC for resected pancreatic cancer compared favorably to historical controls. Induction of anti-CALR Ab after therapy correlates with improved survival. Immunological monitoring of algenpantucel-L immunotherapy with this biomarker is feasible and might predict patient response to therapy. Follow up studies are in progress in a multi-institutional, phase III study which recently completed enrollment.
Algenpantucel-L immunotherapy consists of allogeneic pancreatic cancer cells that have been genetically modified to express the carbohydrate α(1,3)Gal, to which humans have an inherent pre-existing immunity. It is αGal that is primarily responsible for the hyperacute rejection of foreign tissue via this potent immune defense mechanism in humans. Algenpantucel-L leverages this mechanism to educate the immune system towards components of the patients’ own tumor cells. Calreticulin is a calcium-binding chaperone protein that functions in the immune response by folding major histocompatibility complex (MHC) class I molecules and influencing antigen presentation to cytotoxic T cells. In pre-clinical models, drugs that induce cell surface CALR confer enhanced tumor protection. Components of algenpantucel-L express cell surface CALR. Methods: An open-label, 71 patient multicenter phase II study evaluating algenpantucel-L plus standard of care gemcitabine with 5#$%$-XRT for resected pancreatic cancer was conducted. Endpoints included DFS at 1 year, OS, and immunologic analysis. Evaluable patients (n=64) were tested for the induction of anti-CALR Ab by ELISA. Increased titers greater than 20% relative to baseline were considered significant (p