NorthWest Biotherapeutics Inc (NWBO)

[biosectinvestor]

Thanks for the links to the video and more details, you and Lykiri. Here is stuff I have gathered over the years, plus a link to the SPORE grant.

Yes, the video says that, and there is reference someone gave for the NIH funding.

More definitively was the previous trial record at clinical trials.gov which indicates that there had been a trial scheduled, and it was put on hold for contract negotiations. But a review of so much suggests that that trial is likely to move ahead shortly.

I had written also about some research around the early time I started commenting most here, about UCLA's PR about using DCVax-L with the drug PLX3397, which is a drug that is, in fact, a CSF-1R inhibitor.

https://newsroom.ucla.edu/releases/combination-therapy-for-glioblastoma-shows-promising-results-in-early-stage-research

Combination therapy for glioblastoma shows promising results in early-stage research
UCLA RESEARCH ALERT
Reggie Kumar | January 24, 2017
FINDINGS
UCLA researchers have discovered that combining a vaccine developed at UCLA with other experimental therapies and FDA-approved treatments shows promise for reducing the size of advanced brain tumors. The immunotherapy, which is specifically intended to treat brain tumors, is called autologous tumor lysate-pulsed dendritic cell vaccination. It uses a portion of the patient’s own brain tumor and is currently being tested in humans.

In tests in animals, the scientists found that a combination of the vaccine and two different drugs that modulate distinct aspects of the immune system was more effective at allowing T cells to attack glioblastoma than the vaccine alone. The two added drugs were a PD-1 antibody blockade, which enhanced T cell activation inside the tumor, and an investigational drug called PLX3397, which reduces immune suppression within the tumor.

Also see, from 2017: https://www.uclahealth.org/news/combination-therapy-for-glioblastoma-shows-promising-results-in-earlystage-research

Combination therapy for glioblastoma shows promising results in early-stage research
UCLA RESEARCH ALERT

UCLA researchers have discovered that combining a vaccine developed at UCLA with other experimental therapies and FDA-approved treatments shows promise for reducing the size of advanced brain tumors. The immunotherapy, which is specifically intended to treat brain tumors, is called autologous tumor lysate-pulsed dendritic cell vaccination. It uses a portion of the patient’s own brain tumor and is currently being tested in humans.

In tests in animals, the scientists found that a combination of the vaccine and two different drugs that modulate distinct aspects of the immune system was more effective at allowing T cells to attack glioblastoma than the vaccine alone. The two added drugs were a PD-1 antibody blockade, which enhanced T cell activation inside the tumor, and an investigational drug called PLX3397, which reduces immune suppression within the tumor.

BACKGROUND

Glioblastoma is the most common type of malignant brain tumor in adults, and one of the deadliest. More than 12,000 people will be diagnosed with the disease this year, and the five-year survival rate for patients is less than 5 percent. It has a high probability of recurring after treatment and there is no standard therapy for recurrent glioblastoma.

METHOD

The team studied the approach in mice and on tumor samples from human patients.

IMPACT

The findings may point scientists to a process for developing more effective combination treatments for people with glioblastoma and other immunosuppressive cancers.

AUTHORS

The study was led by Dr. Robert Prins, a UCLA associate professor of Neurosurgery and Molecular and Medical Pharmacology and member of the UCLA Jonsson Comprehensive Cancer Center. The first author is Joseph Antonios, a student at the David Geffen School of Medicine at UCLA, andthe co-author is Dr. Diana Moughon, a postdoctoral fellow at the Geffen School of Medicine.

JOURNAL

The study is published in the Journal of Neuro-Oncology.

FUNDING

The research was funded by the National Institutes of Health, the National Cancer Institute, the Isabel Neidorf Foundation, the Musella Foundation for Brain Tumor Research, the UCLA Graduate Division Dissertation Year Fellowship and the UCLA Medical Scientist Training Program.

This is direct from the UCLA Spore Grant page:

Project 1: Targeting immunotherapy-induced resistance with DC vaccination and immune modulation

Project Co-Leaders:
Robert M. Prins, PhD (Basic Science Leader)
Linda M. Liau, MD, PhD, MBA (Clinical Science Leader)

The overall goals of this project are to investigate mechanisms of immune evasion following treatment with dendritic cell (DC) vaccines, and to develop rational combinations of immunotherapeutic strategies to overcome the immunosuppressive milieu of the brain tumor microenvironment. We previously found that, in addition to inducing T-cell infiltration into brain tumors, DC vaccination + anti-PD1 blockade may also create a pro-inflammatory environment within the tumor that induces the immigration of immunosuppressive myeloid cells (TIM). TIM are phenotypically similar to the myeloid cells that attenuate the T-cell response to chronic viral infections, and may counteract the anti-tumor T-cell responses induced by DC vaccination. Therapies that target myeloid cells within the tumor microenvironment represent a promising new strategy. As such, inhibition of these myeloid cells using a CSF-1R inhibitor, in conjunction with autologous tumor lysate-pulsed DC vaccination (ATL-DC) and PD-1 mAb blockade, resulted in significantly prolonged survival in tumor-bearing animals with large, well-established intracranial gliomas. Our hypothesis is that myeloid cells mediate adaptive immune resistance in response to T-cell activation induced by immunotherapy. We have planned a series of novel pre-clinical studies to re-polarize myeloid cells, to optimize how the timing and sequence of immunotherapy can influence ant-tumor immunity, and a new clinical trial to test the first-in-human combination of a new brain penetrant CSF-1R inhibitor (CSF-1Ri; PLX3397, Daiichi-Sankyo) with DC vaccination and PD-1 mAb blockade (Pembrolizumab, Merck) in patients with newly diagnosed GBM. A better understanding of the biology of these cellular interactions will provide insight into more effective ways to induce therapeutic anti-tumor immune responses for this deadly type of brain tumor.

Aim 1: To identify the optimal timing and sequence by which immunotherapy alters the local tumor-infiltrating immune response in syngeneic murine glioma models and in recurrent glioblastoma patients.

Aim 2: To conduct a new first-in-human Phase I clinical trial of ATL-DC vaccination in conjunction with CSF-1R inhibitor (PLX3397) and PD-1 mAb (Pembrolizumab) blockade, and develop predictive immunological and imaging biomarkers.

Aim 3: To elucidate the immunotherapy-induced resistance mechanisms by which immuno-suppressive myeloid cells inhibit anti-tumor immune responses in pre-clinical animal models and in newly diagnosed glioblastoma patients.

Figure for Project 1. Depiction of the critical immune components that regulate effective anti-tumor immune responses for malignant gliomas.
Figure for Project 1. Depiction of the critical immune components that regulate effective anti-tumor immune responses for malignant gliomas.

Additional UCLA research on this drug: https://academic.oup.com/neuro-oncology/article/18/4/557/2509330

Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study

The drug is manufactured by a Japanese company with a NJ Subsidiary, Daiichi Sankyo, Inc., so at the time, in 2017, I expounded frequently about the possibilities of a venture with the Japanese company because of the PR from UCLA. Japan had a program to advance trials quickly in Japan that involve cell therapies. I am not a huge fan of the program now, but it kicked off with great expectations and MESO got an early approval in Japan because of that program. Looks like they have closed the NJ company that invented the drug. https://www.plexxikon.com - so it's all Daiichi Sankyo now.

And of course here is the link to the previously scheduled, and canceled trial with BMS, which it looks like will hopefully be scheduled to start up again soon and which probably will be revised to include PLX3397 or the CSF-1Ri.

BMS / NWBO / UCLA Clinical Trial that had been set aside earlier, probably will now be rescheduled. This may even be one of any number of pending news events. https://clinicaltrials.gov/ct2/show/NCT03014804

Here is a section of the combination patent covering this research.

https://patents.google.com/patent/US20150202291A1/en

"[0169] The inhibitory myeloid population was depleted utilizing Ly6C depleting Ab or the clinically-relevant CSF1r inhibitory drug PLX3397. Depletion of these cells in GL261-bearing mice entirely recovered survival benefit observed in mice treated with DC vaccine/anti-PD-1. Spleen, lymph, and brain hemispheres harvested for processing on day 16 post-implant (72 h after second treatment). The absence of these Ly6C+PD-L1+ cells in the tumor microenvironment was confirmed and noted a significant tumor-infiltrating population of CD3+CD8+CD25+activated lymphocytes. Depletion of CD8+ cells in mice treated with DC vaccine/anti-PD-1 abolished all therapeutic benefit associated with the treatment (FIG. 4 c). Tissue harvests confirmed the absence of activated lymphocytes both systemically and at the tumor site."

And here is the video you guys provided, with a direct link to the specific question and then answer relating to the above.

https://youtu.be/fMxjVRRSdXE?t=2805