Northwest Biotherapeutics: Comments on Two AACR Posters (NWBO, $8.62, Buy)
Introduction
I have included an abstract on DCVax Direct and another on DCVax-L that will be presented in poster presentations at the American Association of Cancer Research (AACR) meeting during April 18 to April 22. I have included the entire abstract for your review
DCVax Direct Poster
This poster dealt with the phase 1 trial of DCVax Direct. In a phase 1 trial, a Company is primarily trying to determine the maximum tolerated dose and the safety profile of its product. Such studies are not designed to demonstrate efficacy in a controlled, randomized manner, but can give sometimes give signals of efficacy. I consider this poster as giving incrementally positive information, but certainly does not define the clinical profile of DCVax Direct.
The patients in this trial were suffering from a number of different types of inoperable solid tumors. When the tumor is inoperable, the prognosis is much grimmer. Surgical removal of as much of the tumor as possible is almost always the first line of treatment for solid tumors. Patients in this trial were at a terminal stage of their disease without viable treatment options and were headed toward hospice. Any indication of a biological effect in just one patient would be scientifically interesting.
Comments on the DCVax Direct Poster
I think that there may be a tendency to read too much into the information in this poster; both from those are bullish on DCVax Direct and those who are negative. It takes many years, actually many decades, to define the profile of a new drug technology like dendritic cell cancer vaccines. This poster gives only an inkling of the information that will come out over the next year as these patients are followed. I think that we will see additional data on DCVax Direct at ASCO during the May 29th to June 2nd meeting. That said, here are some of the comments that I have on the poster:
DCVax Direct Appears to Be Very Safe Allowing for an Increase in Dosing
The maximum tolerated dose has not been reached and there are no dose limiting toxicities. The injection schedule was that injections were given on days 0, 7 and 14, followed by booster immunizations at weeks 4, 8 and 16. Three dose levels, at 2 million, 6 million or 15 million dendritic cells per injection, were tested. Because there appears to be no safety issue, subsequent trials can use more frequent injection schedules and possibly the highest dose of 15 million cells or even more per injection.
In the case of most drugs, efficacy increases with the amount of drug that can be administered so that the dose is pushed to the highest level at which side effects can be tolerated. This suggests that if more frequent injections are given, efficacy will increase and in upcoming trials, there will be more frequent injections. However, in the case of DCVax-L there seems to be a bell shaped response to the number of cells injected. At higher and higher doses, there can be a diminishment of effect. So if this also holds true for DCVax Direct, the question is where are we on the bell shaped curve for dose response?
There Are Encouraging Signals that Immune Response Is Being Boosted
The hypothesis behind DCVax Direct is that it can boost the immune response against cancer. Systemic immune responses were tracked through evaluation of T cell subsets and cytokines in circulation, and through T cell receptor (TCR) sequencing in the tumor tissue and in the periphery. Patterns of immunological reactivity were assessed by pathological scoring on tumor biopsies for 29 patients, and included increasing necrosis in 62% of patients and emergence or amplification of infiltrating T cells in 55%. Analysis of T cell subsets in circulation demonstrated normalization of the CD4/CD8 ratio.
There appears to be strong evidence that DCVax Direct does increase the immune system response in about 55% to 60% of the 29 patient sample. Normalization of CD4/CD8 count is an indicator of increased survival in cancer patients. This is very preliminary data and more extensive clinical trials will be needed to determine the extent of the clinical benefit. This surrogate measures indicate that DCVax Direct may be boosting the immune response in 55% to 60% of patients.
Will DCVax Direct Gain Approval in Solid Tumors?
I feel confident that DCVax Direct does have a biological effect in some patients based on this data and we have some anecdotal evidence that in one pancreatic cancer patient, one sarcoma patient and one non-small cell lung cancer patient that there is a meaningful clinical effect. This is all very encouraging and certainly warrants doing more trials. Indeed, the Company will soon start two phase 2 trials in two different solid cancers. If they are successful, it could be the basis for regulatory approval.
Remember that these are terminal cancer patients with no viable treatment options and that DCVax Direct has an extremely benign side effect profile for a cancer drug. At this point, it is premature to determine the duration of effect of the therapy. Prolongation of life by a few months in perhaps as few as 20% to 30% of patients would probably be enough for approval.
What the Authors Think?
The lead author of the study is Vivek Subbiah of M.D. Anderson. The authors’ conclusions support my comments. They said that “Immunotherapy with partially activated DC’s injected IT demonstrates early signals of immune reactivity even in late stage patients with cancer. Preliminary data support the generation of anti-tumor effects following IT injection of the partially activated, autologous DC’s.”
What May Be The Ultimate Role of DCVax Direct in Cancer Treatment?
The intriguing aspect of this phase 1 trial is that I would expect that inoperable solid tumors would not be the area in which DCVax Direct would provide the most clinical benefit. Its presumed mode of action is to boost the immune response and in these patients the immune system in almost all cases has been damaged by prolonged chemotherapy. I would expect a better effect in earlier stage cancer patients whose immune systems are much better. This remains to be seen,
| Abstract Number: | 2499 |
| Presentation Title: | Clinical and immunopathological effects following Image-guided intratumoral injection of activated, autologous dendritic cells in patients with advanced solid cancers |
| Presentation Time: | Monday, Apr 20, 2015, 1:00 PM - 5:00 PM |
| Location: | Section 26 |
| Poster Board Number: | 11 |
| Author Block: | Vivek Subbiah1, Ravi Murthy1, David S. Hong1, Robert E. Brown2, Robert Prins3, Chitra Hosing1, Mary McGuire2, Aung Naing1, Siquing Fu1, Tina Chou3, Quan Lin1, Richard P. Guevarra1, Anthony Conley1, Indreshpal Kaur1, Funda Meric-Bernstam1, Marnix Bosch4. 1UT MD Anderson Cancer Center, Houston, TX; 2UT Health University of Texas Health Sciences Center, Houston, TX; 3University of California, Los Angeles, Houston, CA; 4Northwest Biotherapeutics, Bethesda, MD |
| Abstract Body: | Introduction: Preclinical models have shown that activated DC’s can effectively clear both injected (local) and non-injected (distal) inoperable tumor lesions. Based on this strong rationale a Phase I trial was designed to exploit this finding in late stage solid tumors. Methods: We designed a phase I study to determine the safety of intratumoral injection of activated DC by administering the product repeatedly until disease progression or unacceptable toxicity, in advanced cancers. Endpoints included maximum tolerated (MTD), dose limiting toxicities (DLT), safety, and immune response criteria (iRC) and RECIST. The treatment consisted of image-guided intratumoral (IT) injections of autologous, activated dendritic cells (DCVax-Direct,). Injections were given on days 0, 7 and 14, followed by booster immunizations at weeks 4, 8 and 16. Three dose levels, at 2 million, 6 million or 15 million DC per injection, were tested. Concomitant, serial biopsies were performed at the time of the vaccination in the absence of toxicity /progression. Systemic immune responses were tracked through evaluation of T cell subsets and cytokines in circulation, and through T cell receptor (TCR) sequencing in the tumor tissue and in the periphery.
The MTD has not been reached and there were no dose limiting toxicities. Two patients experienced Grade 3/4 drug related toxicities : one case of fever and dehydration and one case of systemic inflammatory response syndrome. Patterns of immunological reactivity were assessed by pathological scoring on tumor biopsies for 29 patients, and included increasing necrosis in 62% of patients and emergence or amplification of infiltrating T cells in 55%.
In-depth study was carried out in a patient with therapy-refractory, de-differentiated liposarcoma whose imaging at 12 weeks post initial injection revealed necrosis in the primary tumor and stable lung metastases. Biopsies demonstrated an intra-tumoral inflammatory response consisting of lymphocytes, macrophages and TIA-1 expressing cells, suggesting cytolytic activity. TCR sequencing revealed the presence of shared TCR sequences in the tumor as well as in circulation, demonstrating a systemic anti-tumor response. Analysis of T cell subsets in circulation demonstrated normalization of the CD4/CD8ratio. Conclusion: |
Poster On DCVax-L
This poster is essentially the same information that was presented at ITOC in March, My interpretation of the data can be seen at this link. The full poster is as follows:
| Abstract Number: | 2491 | |||||||||||||||||||||||||||
| Presentation Title: | Treatment with tumor lysate-pulsed autologous dendritic cells prolongs survival in patients with recurrent glioblastoma multiforme | |||||||||||||||||||||||||||
| Presentation Time: | Monday, Apr 20, 2015, 1:00 PM - 5:00 PM | |||||||||||||||||||||||||||
| Location: | Section 26 | |||||||||||||||||||||||||||
| Poster Board Number: | 3 | |||||||||||||||||||||||||||
| Author Block: | Marnix Bosch1, Robert Prins2, Linda Liau3. 1NW BIOTHERAPEUTICS, Bethesda, MD; 2University of California, Los Angeles, Los Angeles, WA; 3University of California, Los Angeles, Los Angeles, LA | |||||||||||||||||||||||||||
| Abstract Body: | Background The survival rate in recurrent Glioblastoma multiforme (rGBM) patients has not meaningfully changed in the past several decades. We have treated two cohorts of rGBM patients, one consisting of patients with early progression, and one of patients with progression following several cycles of adjuvant temozomolide chemotherapy, with autologous dendritic cells pulsed with autologous tumor cell lysate (DCVax®-L). Such treatment is intended to activate the immune system against the tumor cells, so that the ensuing immune attack may delay progression and time to death. Methods Disease progression in patients with GBM was determined through MRI. Progression needed to be determined by independent review on 2 consecutive scans for early progressor classification to avoid enrolling patients with pseudoprogression. Assessment of progression was done using modified RANO criteria. Results Nineteen (19) patients diagnosed with GBM were determined to have recurrence immediately following radiation therapy with concomitant temozolomide chemotherapy. Median overall survival in this cohort from initial GBM diagnosis is 15.1 months (95% CI: 10.5-17.2), and the range is 8.1->31 months. A literature search revealed 6 publications with comparable populations of patients. The table below demonstrates that these patients typically have a life expectancy of 8-10 months.
A second cohort of patients with rGBM consisted of 8 patients with recurrence following several adjuvant temozolomide treatment cycles. Median OS for these patients is 14.7 months from the time of surgery for first recurrence. The comparator for this cohort is derived from Friedman et al. (2009), who reported mOS of 8.7-9.3 months from the time of first recurrence for rGBM patients treated with Bevacizumab with or without Irinotecan. |
Tagged as dcvax direct, DCVax-L, Northwest Biotherapeutics Inc., NWBO + Categorized as Company Reports
Thank you Larry for reading and then commenting on the information that was presented on the 2 posters by the lead scientists on the NWBO treatment for cancer using DC cells….
I do have several questions, but I will limit them…..
I have never been to a scientific meeting and read posters…..so….Could you share with me, What is a poster presentation???…..I guess the scientists or their representatives will be there to answer questions about what has published and people have been reading about….true??
so, will more information be discussed that is not present in the poster???
next…..Who determines what is on the poster and what is left out???? You correctly hoped that more information would be released at ASCO, so makes that decision, the company or the scientists???? The logic of this question is that Ms. Powers has been accused of controlling information and hiding things she does not like…..does she have final say about what is on the poster and what is talked about during the “presentation”???
Thank you and anything you can share with me about what is a “presentation” at these meetings would help me understand what will be happening on Monday….OH, I also wanted to ask you if you knew how much $ it takes to sign up for a “presentation”??? I guess about $100,000 per poster, but could be way off…..Again, thank you for timely and helpful break-down of the 2 posters and what it might mean going ahead……Cheers OH…just remembered….did you glance at the other poster about DC cells stating that they are now being validated when they are matured properly….good poster I thought….cheers again
At Conferences there are oral presnentations that generally last for 15 or 30 minutes. There are also large halls with boards set up to which posters are attached. Presenters stand by the posters and people come along over the course of a few hours and read the poster and talk to the presenter. The presneter may not be there for the whole time. The content is determined by the scientists.
Hi Larry, thanks for reviewing those AACR abstracts.
Here is an additional NWBO “Presentation Abstract” that was added to the AACR conference a few days ago.
“Presentation Abstract
Presentation Title: Clinical Development of Dendritic Cell-Based Therapies for Both Resectable and Unresectable Tumors
Presentation Time: Monday, Apr 20, 2015, 3:00 PM – 4:00 PM
Location: Exhibitor Spotlight Theater B, Halls B-E
Author Block: Marnix L. Bosch. Northwest Biotherapeutics, Inc., Bellevue, WA
Abstract Body: Dr. Bosch will discuss NW Bio’s DCVax® platform technology, a personalized, dendritic cell based active immunotherapy for solid tumors. Unlike conventional cancer drugs and other immune therapies, which use one active agent to hit one target on the cancer, DCVax mobilizes many active agents of the immune system to hit many targets on the cancer.
NW Bio’s lead product, DCVax-L, is designed to treat all types of operable solid tumors. DCVax-L is currently in a 348-patient international Phase III clinical trial for patients with newly-diagnosed Glioblastoma multiforme brain cancer. DCVax-L has also been applied in a Phase I trial with metastatic ovarian cancer, and in various other types of cancers in compassionate use cases. Dr. Bosch will provide updates on the clinical programs and related special access programs.
NW Bio’s second product, DCVax-Direct, is designed to treat all types of inoperable solid tumors, through intra-tumoral injection anywhere in the body. DCVax-Direct is being evaluated in an ongoing 60-patient Phase I/II trial, in which more than 7 different cancers have been treated to date. Dr. Bosch will provide updates about this program and the technology involved.”
I saw that. It looks like something that is for partnering discussions.
Interesting timing for spotlight presentation “UPDATES” on clinical trials and special access programs. Must either be live webcast to the public, which I doubt, or PR must come out prior as presentation is from three to four p.m. EST.
If the updates come after market hours, I assume an 8k may not be done until the next morning before opening bell. I dunno how that works. 100 people attend the spotlight presentations live. I hope we know what they know by 9:25 a.m. EST April 21, 2015.
For anyone interested. Here is a bit more information on the “Spotlight Presentations.” It is elaborate.
http://aacr.org/Documents/15AM_ExhActivities.pdf
Larry and those adding comments and new information….Thank you…..Updates does sound good…only 100 allowed…..hope they have a full house….wonder if it can be web-cast?? Wonder if AF will attend??? doubt it….I really appreciate all the efforts you have made to bring this new science into the homes, hearts and minds of people like me who want to believe that our God constructed immune system can be re-trained and re-organized to seek out and fight the deadly disease that is killing the body…..I am staying tuned and hopeful that progress will be made and that the work of NWBO and others will prevail in the fight against cancer….Cheers