Hope I'm not out of place here but the lower dose, multiple site injection method is how NWBO sought to overcome this issue. The phagocytation of DCs with self antigen near the site of injection left small numbers of DCs to travel to the lymph zone. Good thing that various studies have shown that only small numbers are needed to activate a robust immune response. Eventually this response will be improved upon with isolated, tumor specific activated T-cell subsets that are the most active tumor killers and suppressors. Best wishes.
They are finding that T cells are not responding uniformly to the the well know antigens. But that does not mean they are not responding:
"However, our data, and that of other immunotherapeutic strategies for patients with cancer, suggest that the vast majority of tumor-specific T cells induced by this personalized, patient-specific immunotherapy do NOT recognize well-characterized, known antigens." -- Prins
In order to design the most effective immunotherapeutic strategies for glioblastoma, we believe that it is critical to understand which antigens tumor-specific T cells recognize in this disease. - Prins
Recent information suggests that patients mounting immune responses after immunotherapy can recognize novel neoantigens created by tumor-specific mutations. -- Prins
And Prins hypothesized the same thing in a recent grant application (all the quotes I used were from the same NIH grant):.
"Our hypothesis is that glioblastoma patients treated with autologous tumor lysate-pulsed DC vaccination will mount anti-tumor immune responses against specific mutations in their individual tumor." -- Prins
The immunotherapy is mounting a response to the specific mutations with the cancer. GBM is a cancer that has a decent amount of mutations.
"There are four subtypes of glioblastoma. An extremely large fraction (97%) of tumors in the so-called “classical” subtype carry extra copies of the epidermal growth factor receptor (EGFR) gene and most of these tumors have higher than normal expression of EGFR, whereas the gene TP53, a tumor suppressor gene that has a number of anticancer activities, and which is often mutated in glioblastoma, is rarely mutated in this subtype. In contrast, the proneural subtype often has high rates of alteration in TP53 and in PDGFRA, the gene encoding the a-type platelet-derived growth factor receptor, as well as in IDH1, the gene encoding isocitrate dehydrogenase-1. The mesenchymal subtype is characterized by high rates of mutations or alterations in NF1, the gene encoding Neurofibromin type 1 and fewer alterations in the EGFR gene and less expression of EGFR than the other subtypes."
From this article:
An integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR and NF1
www.ncbi.nlm.nih.gov/pmc/articles/PMC2818769/
By the way, the same article shows this:
"Aggressive treatment with chemo-and radiotherapy has been shown to significantly decrease mortality in patients with classical or mesenchymal subtypes, but has not been shown to significantly alter mortality in the proneural subtypes.
Benefit is derived at more intensive therapy: concurrent chemotherapy and radiation or greater than four cycles of chemotherapy."
And a recent ASCO abstract supports mutation burden:
"Mutational burden and activated T cell infiltration in lung squamous cell carcinomas with DNA repair mutations.
Background: Mutations in DNA repair genes are common in cancer, and may induce a state of hypermutability. Importantly, mutational burden is linked to enhanced response to immunotherapies, as potentially immunogenic neo-antigens may drive a stronger anti-tumor immune response "
But, let's step back for a second and look back at Phase I, pre-2005, and drafting the current IND (with protocol and manufacturing updates). Here's what Linda Liau had to state [mine]:
"So what have we learned so far in last the 7-8 years in writing this [DCVax-L Phase I] trial? What we've learned that these immunotherapeutic approaches can induce tumor-specific immune responses in the host. And we've shown that is possible in objective assays. The Immune response, however, do not necessarily translate to objective clinical responses in brain tumor patients. I think the reason why that is is because of immunosuppressive factor that the brain tumor secretes, and various other factors that are inherent within the host. So I think the host, meaning the tumor patient, and tumor macro-environment needs to be taken into consideration with any of these therapies. " --Linda Liau
"However, not all patient with an increased immune response were necessarily living longer. I think that one problem is that the tumor itself is fighting back. The tumor wants to survive and it secretes factors that is suppressing the immune response. And what we found is that this particular agent TGF-ß2 which is an immunosuppression agent that has been long documented to be secreted by brain tumors, seems to correlate with decreased survival. The one patient that I had that is 5 years out, she essentially had no TGF-ß2 in her tumor, which made her an ideal candidate for this kind of therapy because her tumor was not secreting any immunosuppressive agents that would hinder this immune response from occurring. So in the future, there are trials where we are using combination of agents that suppress, agents TGF-ß2 in combination with vaccine therapies in order to enhance an immune response. -- Linda Liau
And where does that leave us today? Higher peripheral lymphocyte count to predict survival.
And now they have effectively done that. They build a trial to remove more of those responders who might not survive 2 years to see the more robust immunotherapy response. It's smart, really. Enroll an even healthier patient and so, all the patients that are living longer, perhaps in part due to effective surgery and radiation and chemotherapy. But those good odds eventually end for placebo non-crossover patients. However they should also find an increase TIL response inside the tumor from those who make it two years:
"And another thing that we noticed is that patients who live longer, meaning over 2 years verses under 1 year, tended to have more T-cells, these immune cell enter their tumors. Theoretical these tumors are being attacked by the immune system, which is essentially what we want." -- Linda Liau
In the past because the treatments comparison they use were either not necessarily uniform or clearly not equal comparisons. There was much that confounds the data. They never matched a control by the extend of surgery, so that is the aspect of PFS that makes me especially nervous. And so I do think that a healthier immune patient (blood count inclusion /exclusion criteria) with a GTR will end up seeing a prolonged PFS. (What we talked about yesterday.). But I now have a more in depth understanding of what I'm looking at, and I see that their OS remains impressive, as the gains made with surgery to obtain longer PFS does not always translate to longer survival. But again, PFS is the primary endpoint may still be close:
"Although some prognostic factors, such as age and Karnofsky performance status, were relatively matched in our comparison groups, the extent of surgical resection was not directly compared between the patients in this trial and our concurrent/historical controls. Since we need adequate amounts of tumor (>2 grams) to generate the autologous vaccines, tumor resectability was taken into account in the eligibility criteria. Therefore, it is possible that the extent of surgical resection may have been greater in our DC vaccinated patients compared to concurrent/historical controls, which could have influenced our survival results. Nevertheless, the median OS (31.4 mo.) of our DC-vaccinated patients is still noteworthy, when compared to large series of glioblastoma patients who underwent gross total tumor resections and were treated with concomitant chemo-radiotherapy, where the median survival was reported to be 18.6 months. -- DCVax-L Phase I/II
The concern at crossover is that a healthier immune patient will then be more susceptible to mounting an immune attack against the mutations in their cancer, and long tail survival for crossover patients could match their rGBM data. I think the idea is eventually get the okay to use the tumor lysate at recurrence, for patients who qualify for a resection: I was looking for another international abstract that showed a failed a small study that took the lysate of a recurrent patients who had failed chemo patient and pulsed it. (Unfortunately I have thousands of pages of notes in my phone at this point so compiling info to share in a post isn't as easy!) Typically those refractory GBM patients survive but a few months. While it wasn't feasible to get enough lysate in all the patients (outcome of the study), I do remember that one patient surpassed 12 months before progression hit (it was effective when they could). And another 30 months. Here's a study before IMUC started targeting specific antigens (I imagine because it's easier):
IM-20. VACCINATION OF PATIENTS WITH MALIGNANT GLIOMA WITH TUMOR LYSATE-PULSED DENDRITIC CELLS ELICITS ANTIGEN-SPECIFIC CYTOTOXICITY ?John S. Yu, Christopher J. Wheeler, Gentao Liu, Han Ying, William H. Yong, Asha Das, and Keith L. Black; Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
The primary goal of this phase I study was to assess the safety and bioac- tivity of tumor lysate-pulsed dendritic cell (DC) vaccination to treat patients with glioblastoma multiforme and anaplastic astrocytoma. Parameters meas- ured were adverse events, survival, and cytotoxicity against autologous tumor and tumor-associated antigens. Nine patients with recurrent glioblas- toma multiforme and three patients with recurrent anaplastic astrocytoma were treated. One patient with newly diagnosed glioblastoma and one patient with newly diagnosed anaplastic astrocytoma were also included. Patients were vaccinated three times, two weeks apart, with autologous DCs isolated through leukapheresis and pulsed with peptides derived from tumor lysate. Peripheral blood mononuclear cells were differentiated into phenotypically and functionally confirmed DCs. Vaccination with tumor lysate-pulsed den- dritic cells was safe, and no evidence of autoimmune disease was noted. Ten patients were tested for the development of cytotoxicity through a quanti- tative PCR-based assay. Five of ten patients demonstrated robust systemic cytotoxicity as demonstrated by IFN- release by PBMC in response to tumor lysate after vaccination. Using HLA restricted tetramer staining, we identi- fied a significant expansion in CD8+ antigen-specific T-cell clones following DC vaccination in 4 patients, all of whom also demonstrated strong post- treatment antitumor cytotoxicity, as determined by qPCR measurement of IFN message in restimulated PBMC. Six patients underwent reoperation for recurrent tumor. A significant CD8+ T cell infiltrate was noted intratumorally in three of six patients. Patients with recurrent glioblastoma were included in a survival analysis and compared to patients who underwent craniotomy for recurrent glioblastoma at our institution during the same time period. The median survival for the study (n = 8) and control (n = 26) groups was 133 and 30 weeks, respectively (P = 0.0013, log rank). This phase I study demon- strated the feasibility, safety, and bioactivity of an autologous tumor lysate- pulsed dendritic cell vaccine for patients with malignant glioma. We demon- strate for the first time the ability of an active immunotherapy strategy to generate antigen-specific cytotoxicity in brain tumor patients.
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