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“The key observations of this study are, first, that human CD4+CD25hiFoxp3+ Tregs divide rapidly in vivo but have limited capacity for extensive self-renewal, and second, that it is very likely that these cells are continuously recruited from the memory CD4+ T cell pool." In addition, since CD4+CD25hiFoxp3+ T cells have been found consistently to have a highly differentiated phenotype, it is likely that the regulatory cues only have an effect on CD4+ T cells that have been activated to proliferate extensively.”
“In this context, survival factors, such as IL-2, that have been shown to be essential for the generation of CD4+CD25hiFoxp3+ T cells may be effective in part through their ability to counteract the susceptibility of these cells to apoptosis (49–51).” Human CD4+ CD25hi Foxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo . J. Clin. Invest. 116:2423-2433 (2006). doi:10.1172/JCI28941.
http://www.jci.org/cgi/content/full/116/9/2423
"In patients with progressive disease, the mean frequency of Tregs was 7.72% before treatment and increased to 16.7% after the first cycle of IL-2 and remained elevated after cycle 1 (772.3/mL, 9.06%). These increased levels were maintained through the second cycle of treatment (Fig 5C). In contrast, while patients achieving a complete response had slightly higher mean frequency of Tregs (9.0%) before treatment and maintained at a mean of 9.2% after cycle 1, the mean frequency dropped to 1.2% after cycle 2. The differences among the three response status groups are statistically significant with P = .004 (Table 2). Furthermore, this correlation remains significant after adjusting for the ALCs (Table 3)."Data from IL-2 and IL-2R knockout mice suggest that IL-2 is required for the generation and peripheral maintenance of Tregs."Characterization of CD4+CD25+ Regulatory T Cells in Patients Treated With High-Dose Interleukin-2 for Metastatic Melanoma or Renal Cell Carcinoma
Giovanni C. Cesana, Gail DeRaffele, Seth Cohen, Dorota Moroziewicz, Josephine Mitcham, John Stoutenburg, Ken Cheung, Charles Hesdorffer, Seunghee Kim-Schulze, Howard L. Kaufman
From the Tumor Immunology Laboratory, Department of Surgery and Biostatistics, Columbia University Medical Center, New York, NY Journal of Clinical Oncology, Vol 24, No 7 (March 1), 2006: pp. 1169-1177 http://jco.ascopubs.org/cgi/content/full/24/7/1169
One of the primary effects of docetaxel is to interfere with the mitosis of rapidly proliferating cells, leading to their apoptosis. Il-2 is linked to the proliferation of T cells during an immune attack. In other studies CD4CD25 Tregs have been shown to have preferential affinity for IL-2 causing Tregs to increase rapidly at the site of an immune attack, even if not systemically. Tregs not only would have increased susceptibility to docetaxel because of that response, but as the above studies suggest, have limited replicative ability to begin with. Much as in the IL-2 melanoma and RCC studies of Dr. Kaufman et al at Columbia, Tregs should spike in response to an immune attack on a tumor and its microenvironment, but be rapidly depleted by docetaxel to a lower level than at the outset. JMHO.
Another observation that Gold completely missed, IMO, was that Table 7 in the FDA statistical Briefing Materials for the AC, CD54 cell count or upregulation was not statistically significant for survival contrary to what he again suggested at the CC (but is only a manufacturing potency marker as Dr. Prevost correctly and definitely stated at the AC). http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4291B1_03a.htm
Recall that CD54 (ICAM-1) is a marker for mature dendritic antigen presenting cells, which according to Dr. Small's Ph2 study represented a median of about 15% of some 2.4 billion total nucleated cells (TNC)in a Provenge. Per Table 7, TNC cell count was statistically significant for survival.
Again according to the Ph2 study, "The patients’ T-cell and B-cell (antibody) responses to the PAP-GM-CSF construct PA2024 were measured before treatment and every 4 weeks thereafter. The 31 patients had little or no pre-existing T-cell proliferation responses to PA2024, whereas 100% developed T-cell proliferation responses after infusion of Provenge."
"PA2024 consists of PAP fused to the targeting element GM-CSF. T-cell responses to each of these components were examined. No patient had pre-existing T-cell responses to PAP isolated from human seminal fluid; whereas after treatment with Provenge, 10 (38%) of 26 patients developed a T-cell response to PAP."(My comment: DNDN's Ph3 T cell stimulation data was measured by responses to the fusion protein and described as representative of its priming against human PAP, even though the reason PA2024 is used was due to the difficulty in getting T cell stimulation results to human PAP) "Antibodies to PAP and GM-CSF were evaluated by specific ELISA on serum samples obtained at baseline and then every 4 weeks. None of the patients had pre-existing antibodies to PAP (isolated from human seminal fluid); whereas after treatment, 16 (52%) of 31 patients had antibodies." Immunotherapy of Hormone-Refractory Prostate Cancer With Antigen-Loaded Dendritic Cells
By Eric J. Small, Paige Fratesi, David M. Reese, George Strang, Reiner Laus, Madhusudan V. Peshwa, Frank H. Valone Journal of Clinical Oncology, Vol 18, Issue 23 (December), 2000: 3894-3903
http://jco.ascopubs.org/cgi/content/full/18/23/3894
Docetaxel is known to increase the activation of macrophages, which destroy antibody marked cancer cells in a process of phagocytosis. Thus, although never discussed, docetaxel's strengthening of a humoral, antibody related destruction of human PAP expressing cells might be as important as its destructive impact on rapidly proliferating Tregs at a tumor site allowing a cellular, T cell immune attack to become effective since Ph2 data suggests that a higher percentage of human PAP expressing cells reacted to antibodies than T cells. Ultimately, docetaxel's synergistic MofA impact, IMO, benefitting both humoral and cellular immunity is probably quite similar for Provenge and GVAX.
>>I guess Gold could have fielded Monnane's Treg question better and show his depth of knowledge in the field.<<
IMO, shallow waters indeed.
While DNDN diddles around with Neuvenge for years, John Hopkins initiates GVAX in breast cancer. References provided by microcapfun:
http://wjz.com/local/breast.cancer.vaccine.2.568678.html
http://www.clinicaltrials.gov/ct2/results?term=breast+johns+hopkins+vaccine
Gold during CC: DNDN will only be told if Provenge bettered its allocated alpha at the interim look in 9902b in mid 2H08, and if not, only that the trial will continue. How does that tie into any expectation about an interim result greater than allocated alpha but less than statistical significance being "additional clinical efficacy data" reported in the CRL and allow for filing an amended BLA?
His response more or less parallels that of the CEGE CEO. Assuming, for discussion: (1)equivalent results for Provenge and GVAX, and as their CEO projects now, (2)CEGE' Vital-1 interim results in 2Q08, and (3) DNDN's lead in BLA preparation, the race to be the first immunotherapy in AIPC/HRPC will be on. CEGE's Vital-2 interim, where the ITT arm of symptomatic AIPC/HRPC patients takes GVAX and docetaxel together every three weeks, is now projected to occur around 1Q09, implying that the trial should have enrolled its 400th patient recently. My WAG remains that both Provenge and GVAX will receive FDA approval in 2009.
Just to make things interesting: CEGE projects that their interim look for the 600 patient Vital-1 Ph 3 trial will occur in 2Q08. The limited data that is available (n=32) from their ph 2 GVAX in AIPC showed that median survival for the subgroup receiving the high Ph3 dose was 35 months. As of of April, the median survival for the even smaller hi dose GVAX subgroup that received subsequent docetaxel was >35.2 months and had not been reached.The Vital-1 control arm is docetaxel which in the TAX 327 Ph 3 trial reported median survival of 22 to 23 months in asymptomatic AIPC. If the number of events required for the interim is 200 and the allocated alpha p value for the interim is 0.01, what are the chances that Vital-1 will be statistically significant? better its allocated alpha? What if the median survival is only 30 months? The DNDN MB's have the best stat guys in biotech cyberspace. Any inputs would be great.
The following post from the IV Board seems to agree that using the HR of subgroups at an interim look is a good way to determine the outcome at a final look.
http://www1.investorvillage.com/smbd.asp?mb=971&mn=135382&pt=msg&mid=2368325
My comment about Gleasons score was incorrect. One of the 10 prognostic factors in the nomogram was tumor grade, which meant either high or low Gleasons score, Its relevance was similar to the previous Halabi nomogram of 7 prognostic factors, that is, if Glaesons score was at the high end of its range, it added the lowest points (8) to the total sum. The new nomogram included several new prognostic markers including docetaxel use, baseline pain, mode of progression, number of metastatic disease types and PSA Doubling Time that were not included in the Halabi nomogram. However, the concordance index of 0.69 was not an improvement over the Halabi probability of accuracy.The authors conclude that the lack of better predictive ability in spite of the 10 factors that were statistically significant suggests that other important biomarkers have still not been factored in. Regretfully, that probably means that lengthy randomized clinical trials in HRPC with survival as an endpoint will continue to be needed for FDA approval until and unless some composite or standalone surrogate marker(s)with better correlation to patient survival or other meaningful clinical benefit are validated. Given the recent failures of both satraplatin and Asentar, Provenge and GVAX, if either or both are successful, could become new standards of care in AIPC/HRPC for years to come.
Another interesting fact in the study was that at the time of completing the study in November 2006, four years after accrual of the last of 1006 patients in the TAX327 pivotal Ph 3 trial, 800 deaths had occurred, and thus 20% of enrollees were surviving long term, with the longest time to survival in 11/06 being 70.8 months.
Gleasons score was not among the 10 independent factors found to be prognostic for survival in a new study which developed a nomogram based on patients in the Taxotere TAX327 pivotal Ph 3 trial.A Contemporary Prognostic Nomogram for Men with Hormone-Refractory Metastatic Prostate Cancer: A TAX327 Study Analysis
Clinical Cancer Research 13, 6396-6403, November 1, 2007. doi: 10.1158/1078-0432.CCR-07-1036
http://clincancerres.aacrjournals.org/cgi/content/full/13/21/6396
The median survival of the worst quartile studied was about 13.8 months and of the best quartile was about 24.7 months.
Too little of a good thing (macrophage activation) can also be a bad thing.See a new study published in Nature: http://www.nature.com/nm/journal/v13/n11/abs/nm1677.html
and: http://cebp.aacrjournals.org/cgi/content/abstract/15/4/711
One of the distinct impacts of Taxotere according to Dr. Petrylak and others in increased macrophage activation, as opposed to the macrophage inhibition described in these two studies.Taxotere also interferes with mitosis leading to the apoptosis of Tregs rapidly proliferating in response to a T cell based immune attack. Taxotere also reportedly counters the bcl-2 anti-apoptosis expression of AIPC cells. The B cell / antibody marking of cancer cell antigens associated with both GVAX and Provenge also leads to cancer cell destruction by macrophages.All of this suggests that there is good theoretical support for the synergistic effects of immunotherapies and Taxotere even if the combination of Asentar and Taxotere causes serious problems. JMHO.
The Vital-1 and Vital-2 trials are also unbllinded. It makes you wonder in Ph3 trials with survival as an endpoint (and where safety and survival are related) what purpose is served by not reporting more frequently without penalty, especially where the control arm is the standard of care. CEGE is certainly taking a major hit with its Vital 2 combination trial with Taxotere being an obvious contributor to uncertainty in spite of the fact that their data indicated that Taxotere after immunotherapy is highly beneficial, as did the Provenge data and the PFS data of Therion.
Bayer Stops Sales of Trasylol Globally http://biz.yahoo.com/ap/071105/heart_drug.html
Another clinical trial failure,though not in oncology.
The biotech success rate this year is starting to make wildcat oil prospecting a conservative way to invest.
NOVC's drug is a concentrated form of Vitamin D (calcitrol). A look at Wikipedia on Vitamin D both for its beneficial effects in cancer, toxicities, and impact on the immune system is quite interesting.
http://en.wikipedia.org/wiki/Vitamin_D
Surprisingly, while Vitamin D, which sunlight's impact on skin upregulates, has been associated with the higher incidence of prostate cancer in Nordic countries as compared to the tropics, it also causes an increase in regulatory T cells with their immunosuppressive effects. Vitamin D increases the activation of macrophages, which are part of our innate immune systems. Taxotere is also associated with the increased activation of macrophages, as well as its independent effect of impeding the replication of proliferating cells.
Macrophages have been linked to arteriosclerosis and heart disease. One guess might be that the NOVC Asentar safety issue may be a case of too much of a good thing being a bad thing - overactivation of macrophages leading to cardiac problems. http://www.cumc.columbia.edu/news/press_releases/ira_tabas_diabetes_heart_disease.html
http://www.hopkinsmedicine.org/press/2002/September/020915.htm
Asentar's failure may also have some fall-out effect on both Provenge and GVAX since there was some concern about the slight increase in the rate of CVAs with Provenge. However, both use GM-CSF as their immune activating agent, one linked in a fusion protein and the other expressing it from genetically engineered AIPC cells. GM-CSF is an FDA approved standalone agent, however, and has not been assocated with safety concerns which would cause it removal from the market.. Also, Provenge and GVAX are associated with T cell and B cell antigen specific targeting, rather than the systemic non specific activation of innate immunity precipitated by Taxotere and Asentar.
The failure of yet another late stage oncology therapy, IMO, is somewhat of a double edged sword, which makes the ultimate value of a successful cancer therapy and its sponsor that much greater, while making potential partners all the more cautious in the absence of good data. In a safety concious environment, cancer vaccines offer the distinct advantage of low side effects, but as Dr. Petrylak and others have pointed out, they may need the help of Taxotere or other chemotherapies, with their associated side effects, to deal with cancer tolerance caused by regulatory T cells in order to demonstrate significant efficacy. JMHO
The wild card is that the same CTGT section of CBER that handles Provenge also handles the GVAX prostate cancer Vital 1 600 patient trial vs. Taxotere, the standard of care. They may want to compare results. Vital 1 is due to report interim results almost 6 months prior to 9902b, and comparitive results could add confusion. Personally, IMO, both should be encouraged to file/refile a BLA if they reach stat significance on the interim, since it makes stat significance on the final a virtual certainty. A bureacratic FDA, however, could hold both to the requirement to better their allocated lower alpha. Both are helped immensely by subsequent docetaxel, but both seem to have a fear that by acknowledging that fact, they undercut the idealized benefits of immunotherapy. The reality is that CD4CD25FoxP3 and CD8CD28(minus) regulatory T cells can, and have, stopped cancer vaccines cold, but that Taxotere appears to use the proclivity of Tregs for rapid proliferation in response to an immune attack as their weakness to eliminate them.Vital 2 GVAX + Taxotere vs. Taxotere, which will not be fully enrolled until early 2009, though reporting interim results at the same time due to the expected 15 month interim survival in symptomataic AIPC, might have significant results in spite of a greater patient tumor volume since the combination therapy is a requirement of the ITT arm. IMO, both Provenge and GVAX should, and will, receive FDA marketing approval eventually, but the system may be rough on them at their interim survival looks. IMO, they both should be stringently analyzed and compared, but unless some real undisclosed problems surface, should be allowed conditional approval at interim unblinding until final results are in,(once each proves that it can safely and reliably produce it in commercial quantities in accordance with cGMP) if stat significance at the final look is "reasonably likely" (a statutory requirement for conditional approval). There should also be some recognition of the need for subsequent docetaxel to optimize results, if only in the labeling of each. Unfortunately, comfortable and powerful FDA bureaucrats and lofty salaries and options for corporate execs, regardless of performance, seem to make urgency politically incorrect. Unfortunately, the reality may be that the next eighteen months may be relatively uneventful in the approval process for both Provenge and GVAX. JMHO.
A big issue will be whether TTP is measured pursuant to "A Clinical Development Paradigm for Cancer Vaccines and Related Biologics" which was developed by the FDA, NCI and various experts and reported at the February FDA / NCI Workshop on cancer vaccines. http://sabin.org/files/PDF/CVCTWG.clinical.development.paradigm.JIT.2007.pdf
This allows an immunotherapy ramp up period to occur before measuring TTP, giving a three month example. If this approach had been used in 9901 retrospectively, it would have been statistically significant, though 9902a probably would not have been.
ocyan’s recent estimates regarding the interim survival:
http://www1.investorvillage.com/smbd.asp?mb=971&mn=161016&pt=msg&mid=3287742
walkinizer’s lengthy estimate in May concerning the interim survival look:
http://www1.investorvillage.com/smbd.asp?mb=971&pt=msg&mn=115125
Today, the CEGE CEO said that their 2Q08 interim look at the fully enrolled 600 patient Vital 1 trial in asymptomatic AIPC will be looking at Hazard Ratios since it is an event based trial. I went to an old review to see if I could figure that out, assuming perhaps incorrectly, that the allocated alpha that would determine success would be a p value, not a Hazard Ratio: http://aac.asm.org/cgi/content/full/48/8/2787#F1
However, this article, while helpful, didn’t address the issue directly.
DNDN has, of course, disclosed that the Cox regression analysis, sometimes referred to as a Cox proportional hazards analysis, will be used as opposed to a Kaplan Meier log rank analysis for 9902b.
Perhaps, you ,Walldiver, or ocyan, clarsterh, iwfal or some stat pro could clarify how “success”, if it occurs at the interim 9902b look, will be determined and described. TIA.
One of the more interesting statements in the Statistics Section of the FDA Briefing materials for the Advisory Committee was that Provenge’s above median Total Nucleated Cell Count (TNC) had a statistically significant correlation with increased survival, whereas neither cumulative CD54 cell count nor cumulative CD54 upregulation did.CD54 (also known as ICAM-1) is the Provenge potency marker for the presence post ex vivo processing of mature dendritic cells (aka Antigen Presenting Cells or APCs) primed with the PA2024 fusion protein. DNDN made a poster presentation at a scientific conference last year showing apparent preliminary data that above median cumulative CD54 upregulation was prognostic for survival. Provenge is effectively a soup of a patient’s immune cells and in an average dose, only some 20% are APCs. The APCs are believed to prime CD8 effector T cells inducing a cellular th1 mediated immune response.The other immune cells in a Provenge dose include B cells, which in an immune context is related to an antibody, as opposed to a T cell,targeting mechanism and induces a th2 MofA. DNDN has also conducted early Ph1 trials of Neuvenge, which is processed ex vivo like Provenge, using a fusion protein incorporating the HER2/neu breast cancer antigen. A new study published in AACR reports that two experimental vaccines targeting either a antibody or T cell response: “individually conferred only weak tumor immunity. However, efficient tumor rejection was seen when neu and FLneu were combined, inducing both strong anti-HER2/neu-specific antibody and T cell responses. Adoptive transfer of both immune CD8+ T cells and immune sera from immunized mice was required to confer tumor immunity in naïve hosts. “ Antibody and CD8+ T Cell Responses against HER2/neu Required for Tumor Eradication after DNA Immunization with a Flt-3 Ligand Fusion Vaccine Clinical Cancer Research 13, 6195-6203, October 15, 2007. doi: 10.1158/1078-0432.CCR-07-0258 http://clincancerres.aacrjournals.org/cgi/content/abstract/13/20/6195
This may explain why a TNC count of processed immune cells, which includes activated B cells leading to an antibody response as well as APCs priming T cells, may be more relevant to extended survival than APCs alone as measured by their CD54 markers.
This might also suggest that at some point in the distant future DNDN’s Provenge, which has a stronger T cell response but a weaker antibody response against AIPC, may be combined with CEGE’s GVAX, which appears to have a stronger and broader antibody response, but weaker T cell response, to be twice as effective – with either docetaxel of ipilimumab countering the T cell defensive regulatory T cells. JMHO.
A new SEC investigation target, after its backdating investigations caused numerous corporate upheavals an a recent well publicized conviction, is the abuse of 10b5 preplanned selling programs where executives may not only profit from downside risk free options, but also use the timing of 10b5 plans to hide insider trading.
http://www.cfo.com/article.cfm/9217384/c_9389236
http://dealbook.blogs.nytimes.com/2007/10/11/sec-asked-to-investigate-countrywide-chiefs-trading/
"CEO Option Grants Appear Harmful" according to a new study.
http://biz.yahoo.com/rb/071012/column_lifting_ceo.html?.v=1&.pf=career-work
An Ovarian Cancer Vaccine reported today on BBC News and previously reported in July in the Proceedings of the National Academy of Sciences targets the NY-ESO-1 antigen that DNDN once licensed from the Ludwig Cancer Institute.
http://news.bbc.co.uk/2/hi/health/7042410.stm
http://www.pnas.org/cgi/content/abstract/104/31/12837
There recently has been some interesting developments wrt a compound that is apparently synergistic with taxanes and helps them induce apoptosis (cell suicide) on a preferential basis in cancer cells by increasing levels of oxidative stress, which are already quite high in cancer. Although it's being tested in late stage melanoma, there doesn't appear to be any reason that it wouldn't work in other applications where taxanes are being used now. http://www.syntapharma.com/Documents/STA4783_Overview.pdf
SNTA, the developer recently signed a large deal with GSK.http://biz.yahoo.com/bw/071010/20071010005559.html?.v=1
An analyst commented:"In September 2006, Synta reported positive results from a double-blind, randomized, controlled Phase IIb study of 81 patients with malignant melanoma," King said in a note to investors. "This was the first controlled trial in melanoma in 30 years to reach its primary endpoint."
http://biz.yahoo.com/ap/071002/synta_mover.html?.v=1
My comments are not intended as a rec, only that to the extent that the combination of Provenge/GVAX plus Taxotere(docetaxel) may prove to be highly effective, increasing the power of taxanes to kill cancer cells might further increase efficacy in AIPC/HRPC.
These Committed Equity Financing (CEFF) deals seem to be popular in biotech (DSCO, CEGE). They often seem to be more like working lines of credit, equity distribution deals where there are more frequent smaller drawdowns and where the CEFF acts more like a broker of the issuer's shares and large placement fees and discounts, such as the last two DNDN $4.50 offerings, need not occur. In DNDN's case, it makes sense since the trading volume remains high (technically allowing for larger drawdowns) and the company must prudently plan for the worst case possibility that the interim 9902b look might not be good enough for FDA approval, at which point in time, the equity markets could be very difficult. There's a real near term decision point, however, in that, absent some intervening positive news, the ideal time to use the facility to raise the most cash and maintain interim pps levels would be at a time when the disproportionately large short position is attempting to cover with the help of active market makers. Once that short covering is completed, daily trading volume might be substantially lower. Other than keeping a cash reserve for product launch if the interim look is positive or an operating reserve if it is not, it would seem that DNDN must keep a viable production facility in operation. Then, after 9902b is fully treated, what does DNDN do with its output? Would you start a necesssarily small open label trial of Provenge + Taxotere vs. Taxotere, as Dr. Petrylak 11/10/06 presentation would support, as an insurance policy? Would you spend more on basic research to more fully elucidate the Provenge MofA to answer some continuing questions to convince the medical community that Provenge is different from the many previous cancer vaccine failures (for example, the lack of reactivity to human PAP, the impact of Tregs, etc)? Much like CEGE's GVAX, time and money mandate concentrating all resources on prostate cancer, rather than other pipeline development. For the sake of their future patients and for each company, I hope that both DNDN and CEGE are successful, and sooner rather than later.
What's with the values attached to a biotech's net loss carry-forwards? Unless they have recently changed the tax law, tax losses can only be used if the ownership of a company's stock doesn't change; an acquistion by another company generally wipes out the tax loss.
A form of stem cells greatly increases the metastases of breast cancer, but may be controlled by an existing HIV drug.
http://news.bbc.co.uk/2/hi/health/7026843.stm
Reading “between the lines”, Gold’s presentation at UBS today seemed to place emphasis on dealing with an unacknowledged comparison to CEGE. If the FDA had approved Provenge in May, DNDN would have had a clear and substantial first to market advantage with Provenge over CEGE’s GVAX for AIPC/HRPC. Now it’s more of a competitive race. Items noted: (1) DNDN has a FDA inspected (small 12 work station) production facility in Hanover NJ (which the CFO apparently now concedes must be reinspected by the FDA whenever the Provenge BLA is refiled) (vs. a CEGE GVAX cGMP facility in California “suitable for commercial launch” but not yet inspected by the FDA in a preapproval inspection); (2) 3 Provenge infusions over a month (vs. a dozen visits to a doc for multiple GVAX interdermal injections over 6 months); (3) the 9902b Ph 3 trial builds on the 9901 Ph3 trial (vs. CEGE’s projections of a greater GVAX increase in median survival from a smaller group of Ph2 patients given the Ph3 higher Vital-1 dose); (4) 225 Ph 3 patients in 9901 & 9902a and 500 in 9902b (vs. 600 Ph3 patients in Vital 1, with continuing enrollment in, and later reporting, in Vital-2); (5) ongoing Ph3 P11 trial in earlier and larger ADPC patient group (vs. Vital 2 in later advanced AIPC/HRPC, and GVAX better positioned for an earlier approval in the EU); (6) pipeline of Neuvenge in Ph1 for HER2/neu breast cancer, licensed CEA and CA-9 antigens with possible applications in colon, lung and renal cancerand preclinical Trp-p8 work (vs. John Hopkins Ph2 GVAX trials in pancreatic cancer and leukemia and earlier stage GVAX breast cancer planning at JH, CEGE’s internal GVAX lung cancer planning and JV with Novartis on viral oncology therapies); and (7) antigen cassette platform technology processing patients’ own immune cells ex vivo (autologous) with fusion protein linking a single antigen with GM-CSF (vs. allogenic irradiated metastatic cancer cell lines expressing GM-CSF and recruiting immune cells at injection site designed to prime multiple antigens). A competitive race is on, which can only benefit cancer patients, and will, IMHO, eventually lead to FDA approval of both immunotherapy approaches. Even if one or both Provenge and GVAX have good interim data, the time required to refile a BLA in Provenge’ case, or to prepare and file in GVAX’s case, will delay any approval and commercial launch until 2009. Again, IMHO, if either or both immunotherapies achieve statistical significance for increased median survival, but not the higher bar of a lower allocation of alpha, the FDA should allow the refiling/filing of a BLA. FDA agreement in the SPA of each to allow this would be a reasonable and achievable goal of prostate cancer advocacy groups and probably be a quicker and more achievable goal than more generally directed targeting against AC conflicts of interest and FDA banishment of Dr. Pazdur. JMHO.
The importance of dealing with immunosuppressive Tregs in the context of immunotherapy has become the subject of numerous articles over the past several years. An oft cited study from 2005 stated: “Therefore, CD4+CD25+ T cells maintained an environment in the tumor that concealed the immunogenicity of tumor cells to permit progressive growth of antigenic tumors. Our study illustrates that the suppression of antitumor immunity by regulatory T cells occurs predominantly at the tumor site, and that local reversal of suppression, even at a late stage of tumor development, can be an effective treatment for well-established cancers.” http://www.jem.org/cgi/content/full/201/5/779
Another widely cited retrospective study of Epithelial Ovarian Cancer in PNAS found that the greatest indicator of increased survival was the ratio of CD8 T cells to CD4 CD25 regulatory T cells. http://www.pnas.org/cgi/content/full/102/51/18538
Now a new study published in the current issue of the Journal of Immunology analyzing tumor tissue from many different types of cancer reports that a certain subgroup of CD8 effector T cells, CD8+CD28– T cells, are also immunosuppressive: “The unprecedented observation was made that CD8+CD28– T regulatory lymphocytes are almost constantly present and functional in human tumors, being able to inhibit both T cell proliferation and cytotoxicity. CD4+CD25+ T regulatory lymphocytes associate with CD8+CD28– T regulatory cells so that the immunosuppressive activity of tumor-infiltrating regulatory T cell subsets, altogether considered, may become predominant.“ The ratio between other types of CD8 T cells and CD8+CD28– T cells becomes critical; the amount of CD8+CD28– T cells has an inverse statistically significant relationship with survival. These immunosuppressive CD8 cells are preferentially recruited to tumors by chemokines that the tumors secrete. The study concludes that the use of whole cell immunotherapies probably introduces some immunosuppressive as well as effector cells, that it appears appropriate if not mandatory that agents countering the effects of Tregs be used, and the use of biologic agents such as GM-CSF as adjuvants must be evaluated carefully since they have the ability to stimulate immunosuppressive as well effector functions. CD8+CD28– T Regulatory Lymphocytes Inhibiting T Cell Proliferative and Cytotoxic Functions Infiltrate Human Cancers The Journal of Immunology, 2007, 179: 4323-4334. The Journal of Immunology, 2007, 179: 4323-4334. http://www.jimmunol.org/cgi/content/abstract/179/7/4323
This study is just another link in the chain of evidence that further supports the importance of the use of chemotherapy to dramatically increase the efficacy of cancer vaccines and immunotherapies. This can involve the use of cyclophosamide to deplete Tregs prior to the infusion of adoptive T cells, such as used in melanoma by the NCI’s Steven Rosenberg and colleagues, or, where priming of T cells is required, as in the case of Provenge and GVAX , by docetaxel that both attacks rapidly proliferating cells, such as CD4CD25 Tregs reacting to a CD8 effector T cell attack and can destroy fixed cancer cells and CD8+CD28– T cells in tumors through the innate immune system’s phagocytosis destruction of target cells.
Despite the popular appeal of believing that immunotherapies with low toxicity can break immune tolerance to cancer and achieve widespread efficacy in significantly increasing survival in HRPC without the help of chemotherapies such as cyclophosamide, docetaxel and others, IMHO, the data on the use of the combination therapy of cancer vaccines and docetaxel in HRPC clearly trumps that of either alone. A few lucky HRPC patients may achieve major increases in survival using immunotherapies alone, but the 9901 and 9902a data strongly suggests that those patients on the average do far worse in terms of both median and 36 month survival than those using combination therapy. In this supposed new era of adaptive clinical trials, therapy choices of future patients would clearly benefit from a subgroup analysis of combination use of vaccines and docetaxel (which , in the case of 9902b and Vital 1, could be prospectively specified as an alternate regulatory path to approval), such as Dr. Petrylak presented last November, as compared to either therapy alone, even where the subsequent use of docetaxel (and possible vaccine boosters) is “uncontrolled”, but data is available from treating docs. In addition, it is possible that patients receiving vaccine and docetaxel might achieve clearly statistical significance in median survival, whether compared to an allocated alpha or 0.05, at the interim look, while vaccine only patients or the composite of combination and vaccine only patients might not. Statistical purists and FDA traditionalists might argue against “too many bites of the apple”, but one can hope that ultimately the FDA would put the interests of dying patients first and allow a regular or conditional approval of a combination therapy subgroup if it shows statistical significance for increased survival, even if the ITT group as a whole did not.
Astra Zeneca (AZN) reports encouraging overall survival data for HRPC patients in a Phase 2 trial for ZD4054, an experimental endothlein A receptor antagonist with a claimed 7.2 month increase in median survival of treated patients over placebo patients. However, there were disappointing progression free survival results. AZN plans three Phase 3 studies in metastatic and non metastaic HRPC and in combination with docetaxel in metastaic HRPC. http://biz.yahoo.com/prnews/070925/netu068.html?.v=23
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UK approves new genetic test for prostate cancer. The Gen-Probe Progensa urine test, which targets a gene that is overexpressed in prostate cancer, PCA3, will possibly eliminate the need for biopsies to confirm a diagnosis after a PSA test.
http://news.bbc.co.uk/2/hi/health/7006107.stm
Dr. Ralph M. Steinman, 64, of Rockefeller University, the scientist who first identified dendritic cells is awarded a Lasker prize. http://www.nytimes.com/2007/09/16/health/16lasker.html?hp
With all the prior publications describing the importance of "costimulation factors" to the proper priming of T cells and to enhance T cell responses to specific tumor Ags, including the development of the rf-TRICOM costimulation compound(ICAM-1, B7.1, and LFA-3), jointly developed by the NCI and the now defunct Therion Biologics), a new publication coauthored by Dr.Jeffrey Schlom of the NCI reports: "Our results demonstrate for the first time that enhanced costimulation can actually restrict both the proliferative response and cytokine production of effector/memory CD8+ T cells in response to activation by low-affinity Ags. This decline in activity of effector/memory T cells is associated with high expression of ICAM-1 on APCs. Moreover, the generation of effector/memory CD8+ T cells with a high-affinity Ag in the presence of enhanced costimulation led to decreased CTL activity, without affecting the proliferative response or cytokine production of these cells." ICAM-1 is also known as CD54, the upregulation of which DNDN once thought was related to increased survival.Enhanced Levels of Costimulation Lead to Reduced Effector/Memory CD8+ T Cell Functionality1
Sven Mostböck*, Silvia Vidal, Jeffrey Schlom2,* and Helen Sabzevari, The Journal of Immunology, 2007, 179: 3524-3534.
http://www.jimmunol.org/cgi/content/full/179/6/3524
The report further states:"In a cancer setting, high levels of costimulation could enhance the interaction of naive T cells with weak epitopes and lead to generation of large numbers of CD8+ T cells with low affinity. However, the same weak epitopes in conjunction with high costimulation could blunt the ability of high-affinity memory T cells to attack the tumor. The compromised effector function induced by APLs can favor tumor escape at the level of memory T cells. Therefore, this information is critical for designing therapeutic strategies for enhancing the immune responses in a variety of diseases, such as cancer." Doesn't sound like a good choice and could explain why the NCI/Therion PROSTVAC vaccine using TRICOM costimulation produced such a weak response (T cell stimulation index of 3.3) against PSA, its targeted antigen. Shows that luck as well as hard work and brains are needed in developing new therapies.
I recently asked the same questions of an oncologist with some background as a clinical investigator.His answers, while general, were along the following lines;
1. Clinical investigators with experience in a given life threatening disease on a Data Safety Monitoring Board would be expected to be sensitive to any trend in safety or clear lack of efficacy or exceptional evidence of efficacy, especially if a trial were unblinded. If any of those circumstances were to arise, they could be expected to bring it to the attention of the sponsor and the FDA. A close call on the efficacy question would be unlikely to give rise to early termination, but clearly poor or outstanding results may.
2. The second question would relate to two issues: both the size of the trial and whether or not there was any dosing and duration records on subsequent docetaxel treatment (The Provenge AC Briefing Materials suggested there were none, except a basic yes/no on subsequent chemo or taxane use). A retrospective subgroup analysis is hypothesis generating. However, retrospective subgroup analyses are expected to show comparable benefits among all subgroups (for example, that there are no well defined subgroups for which there are little or no treatment effects).In a relatively small trial subgroup testing becomes particularly difficult and relatively unreliable.That goes to a general bias for larger trials especially where there are other statistical issues.
While these answers seemed sensible, they are quite general and are not completely reducable to specific numbers. As I stated, I am neither a statistician, medical doctor or clinical investigator. Just a discussion, FWIW, that I thought interesting and somewhat relevant.
iwfal and ocyanblue and any stat experts, some questions:
The premise, as I (mis?)understand it, is that in a life threatening disease in a clinical trial using an event based Kaplan Meier log rank all cause survival analysis, the designed power of a trial assumes a predicted treatment effect and estimates the number of deaths at a given power that may be required to discern the treatment effect in the ITT arm vs. the placebo or standard of care in a control arm. As a result, an interim look with a substantially lower number of events is not expected to be statistically significant, but if the sponsor desires an interim look (for example, to allow a cost avoiding termination of a trial for futility) and continues the trial, an alpha allocation is deducted from the normal statistical significance to account for having a second look, even though bias, post the interim look, should not be a problem in a survival trial. If the treatment effect proves to be statistically significant at the interim look, wouldn't this be possibly due to a greater treatment effect that was used in the power calculation. Theoretically, why would the FDA have any problem allowing earlier termination and the filing of a BLA /NDA due to an unexpectedly efficacious treatment effect?
Another question wrt statistically significant evidence of a combination therapy vs. a standalone therapy where post therapy use of a combination agent was not controlled. At 2006 ASCO, Dr. Small presented an analysis for 9901 that showed that the control patients as a group received some 15% more post Provenge docetaxel than the ITT group, presumably to support the hypothesis that post Provenge docetaxel was not a factor in the increased median survival of the ITT arm as compared to the control arm. Dr. Petrylak’s presentation on 11/10/06 seemingly refutes this ,showing that when compared to the Halabi nomogram reference, the 51 of 147 9901 and 9902a ITT patients receiving some combination of Provenge followed by docetaxel had increased median survival of 13.6 months compared to 5.8 months for the actual over predicted Halabi derived median survival of 5.8 months as reported by Dr. Small for the 9901 ITT group, suggesting that the increase in median survival of the 96 Provenge only 9901 and 9902a ITT patients per the Halabi nomogram might be less than 2 months. The dose and duration of post Provenge docetaxel was not reported. In the lower dosed 9901 and 9902a crossover control group, 31 of the 59 crossover patients who received docetaxel after Provenge appear to have accounted for all the increased median survival. As far as I can see, the Petrylak analysis was not included in the Briefing Material for the FDA Advisory Committee meeting for Provenge. The AC panel was, of course, asked whether there was substantial evidence of Provenge efficacy , rather than substantial evidence of the efficacy of the combination of Provenge and docetaxel. Given the aversion of many AIPC / HRPC patients to docetaxel therapy, one can imagine some patients hesitating to commit to the combination therapy. OTOH, a projected 13.6 months increase in median survival for the combination might persuade more men to start the combination therapy when asymptomatic since there is no evidence that the combination would be effective for sicker symptomatic patients. Given your experience in statistics, how would a statistician decide whether the standalone use of Provenge in asymptomatic AIPC/HRPC would be approved by the FDA vs. the combination therapy of Provenge plus Taxotere, or both or neither? Could this have been one of the reasons for the FDA approvable letter?
Interesting post from the IV MB wrt filing a NDA if results of an interinm analysis are statistically significant. With 9902b, Vital-1 and possibly Vital-2 reporting interin results in 2008, it could be an interesting year for cancer immunotherapies.http://www1.investorvillage.com/smbd.asp?mb=971&mn=154080&pt=msg&mid=2940983
Back at the 2005 ASM, DNDN said that it would be meeting with Genentech (DNA) to discuss several matters, including Neuvenge and Herceptin (and probably Trp-p8). Shortly thereafter, DNA announced that they were developing a "conjugated" hmab form of Herceptin which attaches a compound that kills cancer cells to eventually replace the present "naked" hmab form of Herceptin. This development was expected to further improve Herceptin efficacy; very little was said about Neuvenge therafter. There have also been other compounds (lapatinib?) that also target the same receptor. As a result, HER2/neu breast cancer, which was once considered the most deadly, has reportedly become one of the most treatable with median survival running to some 5 years - good for patients but tough for survival based clinical trials. There must be other breast cancer antigen targets that DNDN, CEGE or the adoptive T cell therapies of the NCI can target that would have greater impact on overall breast cancer mortality. There is also growing evidence that when used in proper sequencing with chemo to deplete regulatory T cells (cyclophosamide, taxanes) cancer vaccines and immunotherapies may actually prove effective in advanced stages of cancer. This could allow clinical trials for their use as salvage therapies, which would greatly accelerate the normal time required for regulatory approval. JMHO.
Dosing and Docetaxel: If you read the Phase 2 report of GVAX in HRPC by Dr. Small et al at http://clincancerres.aacrjournals.org/cgi/content/abstract/13/13/3883 which analyzes the smaller (32 patients) of the two Phase 2 studies, the strong inference is that the efficacy of this immunotherapy depends on both the highest available dosing and subsequent therapy with docetaxel.
Does this observation have any applicability to Provenge? We know from many sources, including the Briefing Materials for the Provenge Advisory Committee that the placebo / crossover patients in the 9901 and 9902a Provenge trials received one third less Provenge dosing than the ITT patients since the first on the three apherisis products was sent back to the placebo patients without processing in order to maintain blinding, while the remaining two apherisis products were frozen for later processing should a placebo patient chose to receive Provenge on the crossover protocol upon disease progression. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4291B1-00-index.htm
We also know from the same source that both the ITT and crossover placebo patients who chose docetaxel therapy after Provenge commenced it at about the same point in time after randomization (debunking a spurious theory put forth by Jonathan Ashcroft that the ITT patients received docetaxel earlier). We also know from Dr. Petrylak’s presentation in November 2006 to the Chemotherapy Foundation that the interval between completion of Provenge therapy and starting docetaxel generally ranged between 4 and 6 months. See: his presentation under GU listing at: http://chemotherapyfoundation.org/professional_education/meetingarchives_tcf2006_main.html
Dr. Petrylak reported that the 51 of 147 ITT patients who commenced docetaxel therapy after Provenge had an increase in median survival of 13.6 months over that predicted for the same patients using the Halabi nomogram. The Halabi nomogram is based on a study of 1100 HRPC patients using 7 weighted diagnostic factors prognostic for survival during the period 1991 to 2001 when there were no FDA approved therapies extending survival. 31 of the placebo crossover patients also received docetaxel after their 2/3 dosing of Provenge. The increase in their actual survival over that predicted by the Halabi nomogram was 5.5 months or about 40% of that of the ITT Provenge plus docetaxel group.
Going back to the AC Briefing Materials, the statistical section stated that there was a correlation between increasing CD 54 cell count (a dosing potency marker) in the 9901 trial and improved Hazard Ratio and survival, although it did not reach statistical significance - further lending credence to the importance of the dosing amount of Provenge given a patient. In addition, the analysis pointed out that the 9901 survival curves begin to separate at 8 months post randomization, which schedule-wise ties into the early post Provenge use of docetaxel. The Briefing Materials also stated that 15% more of the 9901 placebo group received subsequent docetaxel than its ITT group (the percentages for the 9902a ITT and control groups were about the same). This statement as a standalone conclusion is somewhat misleading if it is meant to convey the impression that the use of docetaxel subsequent to Provenge was not a significant confounding factor since controls received a higher percentage than the ITT group. When dosing is factored in per the Petrylak analysis, all of the placebo group would have to crossover to Provenge and then their percentage using docetaxel would have to be 2.5 times that of the ITT group in order for the subsequent use of docetaxel not to be a confounding factor. This may have important ramification for the interim 9902b survival results; it is extremely unlikely that any overwhelming preponderance of both 100% crossover Provenge and subsequent docetaxel use favoring the control group will occur, thus maintaining a strong treatment bias in favor of the 9902b Provenge ITT group.
All of this further ties into one of the Dr. Small’s conclusions as the the Implications for Clinical Practice in one of his last Provenge presentation in October 2006 that Provenge “should not be viewed as replacement for chemotherapy, but as another treatment option." http://investor.dendreon.com/medialist.cfm
It is somewhat surprising that the Petrylak analysis, which was formerly presented on 11/10/06 prior to the 11/15/06 submission of the final BLA, or some summation of the Petrylak data, was not included in the AC Briefing Materials and was not discussed at all in the Advisory Committee meeting. While it may be true that it would be based on a retrospective subgroup analysis that may have lead to less than favorable survival plots of the ITT and placebo groups not receiving subsequent docetaxel , the data is so overwhelmingly positive for the combination therapy of Provenge plus docetaxel and would be viewed as a supplement to the existing standard of care, docetaxel, that even Drs. Scher and Hussein and Provenge’s unknown skeptics within the FDA might have been convinced of the wisdom of conditionally approving Provenge and docetaxel as a combination therapy. Some of the likely unrealistic luster as Provenge being the first immunotherapy to banish chemotherapies might have been lost, but the benefit to patients from earlier access to the combination therapy would have gained. JMHO
The International Society for the Biological Therapy of Cancer (ISBTC) is one of the world's most highly regarded scientific cancer realted organizations. The NCI's Dr. Steven Rosenberg is the editor of its official publication, the Journal of Immunotherapy, and Dr. James Mule', the chair of the Provenge FDA Advisory Committee, is a co-editor.
The annual meeting of the ISBTC will ne held in Boston in early November. See:http://www.isbtc.org/meetings/am07/complete_schedule.php
Last year, DNDN made a poster presentation on CD54 upregulation. Things are different this year. The last invited speaker at the meeting is DNDN's David Urdal, after which an hour and half is devoted to a "Hot Topic", "The Dendreon Debate". I guess if they really wanted to spice things up a notch, as Emeril might say, they could invite Dr. Richard Pazdur to speak and participate in the debate, providing bodyguards free of charge of course.
These conferences seem to confirm that additional clinical trial results in 2008 should make it an interesting and important year for cancer immunotherapy.
The Cancer Vaccine Consortium's Annual meeting will be held in Bethesda, Maryland at the end of September. See: http://www.sabin.org/files/PDF/CVC2007_preliminary_program.pdf
Given the multitude of scientific conferences held each year, the importance of many is merely in networking. Given the list of speakers, CBER regulators, competitive regulated companies, the NCI, including its seeming point man for cancer vaccines, Dr. Schlom, the May CRL for Provenge, upcoming Phase 3 results for MEDX/BMY's ipilimumab, and interim Phase 3 results for Provenge and GVAX in 2008, this one may be different. The scheduled speaker for DNDN's presentation on The Sipuleucel-T Experience is Elizabeth Smith, the capable overall "emcee" for the Provenge AC meeting, but not a doc or scientist as far as I know. It should be an interesting challenge for her wrt how best to summarize the regulatory experience without discussing in more detail the unpublished CRL and Form 483, in the presence of CBER officials no less.
There are also some presentations concerning FDA approvals of combination therapies, which may bring into better perspective the comments of the NCI's Dr. Niederhuber, that the first immunotherapies to receive FDA approval will be combinations and whether this ultimately will be how both Provenge and GVAX receive initial FDA approval.
Nature Reviews Cancer reported this month on another factor that possibly mediates prostate cancer metastasizing to Bone:
Prostate cancer
A secreted isoform of ERBB3 promotes osteonectin expression in bone and enhances the invasiveness of prostate cancer cells
Chen, N. et al. Cancer Res. 67, 6544–6548 (2007)
Article
Prostate cancer preferentially metastasizes to bone. Previously, a secreted isoform of ERBB3 (p45-sERBB3) was detected in metastatic prostate cancer cells isolated from patients and was shown to interact with osteoblasts. Chen et al. now show that p45-sERBB3 stimulates mouse bone to secrete factors including osteonectin, which increases the invasiveness of prostate cancer cells in vitro. Invasion induced by p45-sERBB3 was also blocked by osteonectin antibodies. Thus, p45-sERBB3 and osteonectin might mediate the interactions between metastasizing prostate cancer cells and bone.
http://www.nature.com/nrc/journal/v7/n9/full/nrc2225.html#Prostate-cancer
A basic problem in Vital 1 is that the use of Taxotere after GVAX is not controlled, so that Vital-1 may be a GVAX plus Taxotere vs. Taxotere to some extent as well as Vital 2, making an apples to oranges non inferiority trial impossible.
At present the NCI immunotherapy protocol used in end stage melonoma by Dr. Rosenberg and his colleagues, which depletes T regs with cyclophosamide before infusing a patient's cloned genetically engineered T cells primed against a melanoma antigen, with complete remissions of large vascularized tumors of close to 50%, is generally conceded to be the most successful immunotherapy to date.The many articles about variations of it concede the critical importance of countering the immunosuppressive effects of Tregs. Since both Provenge and GVAX require the priming of T cells, which are also depleted by cyclophosamide, preconditioning a patient before these vaccines won't work. OTOH, Tregs which normally constitute around 5% in healthy men, and are somewhat higher in AIPC patients, proloferate rapidly during an immune attack to levels as high as 25%, for example, in the course of high dose IL-2 therapy. Taxotere preferentially attacks rapidly proliferating cells such as these Tregs, and its method of killing cells is different from that of T cells, which must form synpases with target cells and inject granzyme and perforin. These characteristics of Taxotere makes it somewhat uniquely able to reduce Treg immunosuppression after vaccine CD8 effector T cell priming as Dr. Petrylak pointed out in his presentation of the use of Taxoere after Provenge last November.
It is possible that neither Provenge nor GVAX would be statistically significant for an increase in median survival in their clinical trials as compared to Taxotere without this synergistic boost afforded by their use with Taxotere. See my comments at: http://www1.investorvillage.com/smbd.asp?mb=971&mn=150114&pt=msg&mid=2787782
However, the increase in median survival in AIPC patients seen in the Provenge integrated 9901/9902a trial data and in the GVAX Ph2 data as compared to that predicted by the Halabi nomogram, in both cases where subsequent Taxotere use was allowed, suggest that both therapies used in combination with Taxotere should eventually be approved by the FDA. Time, incuding that necessary to master manufacturing issues, will tell.
FWIW, I presently have no position in either DNDN or CEGE.
I misunderstood this statement:"Even if the MS for the GVAX arm is 30.7 months, there is still a 20% chance it won't be stat sig superior to Tax." Assuming the MS for GVAX is 30.7 months and the Taxotere MS arm is 23 months and where there are 300 patients in each arm, I'm confused as to why GVAX wouldn't be stat significant. It would seem that if those numbers held, the Vital-1 trial would have more power to be stat significant than the 500 patient 9902b trial based on the 4.3 month increase in MS of the integrated 147 patients of the Provenge 9901 and 9902a trials.
Good points, although I don't think that an 80% chance of success for GVAX in Vital-1 is too shabby.
The only supportive care that has been proven to extend survival is Taxotere. Therefore, I would suppose that Ph 2 GVAX patients at John Hopkins would have been offered that therapy, which relates back to the fact that post immunotherapy Taxotere may be an important factor in both Provenge's 9902b trial and Vital-1.
GVAX may be the first allogenic immunotherapy to have reached a Phase 3 randomized trial, so the jury is still out on that approach. For whatever reason, there seems to be more accessible literature on the single targeted antigen, predominently T cell based approach of Provenge. The following is one of the few good discussions that I've come across of the GVAX approach by a non CEGE doc:
http://www.extendmed.com/capvaccine/p7info.html
One final GVAX observation that I noted concerning CEGE's Vital-2 GVAX + Taxotere vs. Taxotere trial is that after the ITT group completes their combination treatment, they receive boosters for life. Dr. Petrylak recommended that DNDN consider such Provenge boosters after completion of Provenge/Taxotere combination tretment last November.
In any event, between Provenge and GVAX, the next two years should be crtical ones for present and future AIPC patients and for DNDN and CEGE.
The abstract of the original article is at:http://cancerres.aacrjournals.org/cgi/content/abstract/67/16/7893
An earlier, interesting complete article on the B7-H3 biomarker is at: http://www.pnas.org/cgi/content/full/101/35/12969
This earlier article implicates the biomarker in osteoblastic tumor growth as well as in immunosuppression. Some 90% of all AIPC is osteoblastic rather than osteolytic, meaning skeletal destruction comes from bone growth rather than cellular death.
The Kwon article appears somewaht unrelated to any Provenge applicability, except to suggest that as a therapy, as opposed to a diagnostic, it may be a better antigen target than PSA, PMSA or Prostatic Acid Phosphatase, the Provenge antigen target, especially since bone lesions have proven to be particularly resistent to regression or remission, whether by immunotherapy or chemotherapy. Perhaps in the rare cases where that has happened (once reported in the Ph2 trials of Provenge at Mayo, and once in a Ph1 combination trial of GVAX and ipilimumab), it may possibly have been the result of antigen cascade/epitope spreading where a different antigen than one targeted is attacked through a secondary immune reaction. Unfortunately, any FDA approved therapy building on this study will involve years of preclinical and clinical testing.