Dexamethasone limits benefit of Immune checkpoint blockade

 New study published in clinical cancer research:

Concurrent Dexamethasone Limits the Clinical Benefit of Immune Checkpoint Blockade in Glioblastoma

https://pubmed.ncbi.nlm.nih.gov/33239433/

from the abstract:

Results: Despite the inherent responsiveness of GL261 to immune checkpoint blockade, concurrent dexamethasone administration with anti-PD-1 therapy reduced survival in a dose-dependent manner. Concurrent dexamethasone also abrogated survival following anti-PD-1 therapy with or without radiotherapy in immune-resistant CT-2A models. Dexamethasone decreased T-lymphocyte numbers by increasing apoptosis, in addition to decreasing lymphocyte functional capacity. Myeloid and natural killer cell populations were also generally reduced by dexamethasone. Thus, dexamethasone appears to negatively affect both adaptive and innate immune responses. As a clinical correlate, a retrospective analysis of 181 consecutive patients with IDH wild-type GBM treated with PD-(L)1 blockade revealed poorer survival among those on baseline dexamethasone. Upon multivariable adjustment with relevant prognostic factors, baseline dexamethasone administration was the strongest predictor of poor survival 

Conclusions: Our preclinical and clinical data indicate that concurrent dexamethasone therapy may be detrimental to immunotherapeutic approaches for patients with GBM.

The GL261 referred to is a mouse model of glioma.

Major study of hypermutated gliomas published in Nature

Mechanisms and therapeutic implications of hypermutation in gliomas.
https://www.ncbi.nlm.nih.gov/pubmed/32322066
https://sci-hub.tw/10.1038/s41586-020-2209-9  (sci-hub link to the full PDF document)

Unfortunately this study provides negative evidence to the idea that hypermutated gliomas would be more responsive to treatment with PD-1 blockers such as nivolumab and pembrolizumab.

from the study
"MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. "

"Because our prior analyses indicated that patients with hypermutated gliomas might have reduced survival, we used a second set of historical controls to compare the outcome of hypermutated gliomas treated with PD-1 blockade versus other systemic agents. Unexpectedly, we observed a longer median OS for patients treated with other systemic agents when compared to those treated with PD-1 blockade"

However, the mismatch repair deficient, hypermutated tumor cells were sensitive to the chemotherapy agent CCNU (lomustine).

"We next treated native and engineered isogenic MMR-knockout glioma models with temozolomide or the nitrosourea lomustine (CCNU), a chloroethylating alkylating agent that generates DNA interstrand crosslinks and double-strand breaks (Fig. 2c, Extended Data Fig. 8g–i). All MMR-deficient models were resistant to temozolomide and sensitive to CCNU, consistent with the lack of hypermutation in samples from nitrosourea-treated patients"


This confirms advice I've given to patients with temozolomide-driven hypermutated recurrent gliomas: CCNU (lomustine) chemotherapy is probably the best choice in terms of conventional chemotherapy options.  However it argues against advice that PD-1/PD-L1 blockade (drugs such as pembrolizumab or nivolumab) would be the best option.

Tumor Mutational Burden and response to immunotherapy

Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers.
https://www.ncbi.nlm.nih.gov/pubmed/28835386


This study was a collaboration between UC San Diego, and Foundation Medicine.
Response rate, progression-free survival and overall survival following immunotherapies (in general, or specifically for immune checkpoint inhibitors such as anti-PD-1/PD-L1) was increased in patients with higher tumor mutational burden (as determined by genetic sequencing).


My commentary:
Newly diagnosed gliomas including GBM usually have low tumor mutational burden.  At highest risk for high tumor mutational burden (hypermutation) are likely those with MGMT-methylated tumors that recur following standard TMZ chemotherapy.

Pembrolizumab (Keytruda) is approved by the United States FDA, among other indications, "for the treatment of adult and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. "

The very high mutational burden sometimes seen in recurrent gliomas following temozolomide chemotherapy is often caused by mutations in one or more of the mismatch repair genes (MHS2, MSH6, MLH1, PMS2).  Having genetic sequencing performed (in North America by Foundation Medicine or Caris, or different companies in other countries) for recurrent post-temozolomide grade IV tumors (especially MGMT methylated tumors) could be a worthwhile way to detect hypermutation/mismatch repair deficiency/microsatellite instability and get access to pembrolizumab outside of a trial.  I can't comment on how easy getting coverage would be (both for the genetic testing as well as the pembrolizumab), as it would in part depend on the policies of the various insurance providers.

Treatment options post-RT/TMZ phase for IDH1 mutated, MGMT unmethylated GBM

Hi all,

I was diagnosed in late September with a GBM (frontal, left, with large cyst, IDH1 mutated, MGMT unmethylated), which was subsequently successfully operated (gross total resection) at the end of September. I guess as many/most here, I eventually stumbled across Ben William's book, the Glioblastoma Treatment options guide and ultimately this invaluable blog and community, which I have been studying and following closely since. I recently concluded the first phase of my treatment, following standard Stupp Protocol (6 weeks concomitant RT/TMZ) and am currently planning next steps (plus waiting for first post-RT MRI next week...).

While I did not get 'smart' in time to save my tumor material from being paraffined post-OP (unbelievably, this is still standard practice here in Germany in most hospitals), I did actively supplement my first phase of treatment with what I think is a reasonably aggressive 'cocktail' approach, including the following components:

--------------------------------------------------------------------------------------

Meds:
- Chloroquine, 1x 250mg
- Celebrex, 2x 200mg
- Disulfiram, 1x 250mg - 500mg (+4mg copper)
- Sativex (THC/CBD spray), ca. 3-4 sprays (approx. 15-20mg)

In general, I tolerated these medications without any major problems or side effects, with a few exceptions. Notably, towards the end of the treatment I developed some peripheral neuropathy in my left foot, which has now almost recovered, however (took around 3-4 weeks to recover). Nevertheless, it cause me to cease the Chloroquine and Disulfiram shortly before the end of my RT treatment phase. In addition, I found it a little hard to tolerate Sativex as I wasn't too keen on the psychoactive effect, which gave me some anxiety / mild panic attacks from time to time at night. As a result, I took it only for around 3 weeks or so.

Supplements:
- Berberine: 1000mg
- Boswellia Serrata: up to 4400mg (gradually increased dosage over course of RT to protect from Edema)
- CBD oil (8%), 5 drops (started after ceasing to take Sativex)
- PSP, 2100mg
- Curcumin (Longvida), 2000mg, increased to 3000mg towards end of treatment
- Green Tea Extract, 3625mg
- Lycopene, 20mg
- Matiake D-Fraction Pro, 65mg (3x 23 drops)
- Melatonin, 20mg
- Omega 3 DHA/EPA, 3528mg
- Probiotics, ca. 40bn units
- Pterstilbene, 250mg
- Resveratrol, 500mg
- Selenium, 200ug
- Silymarin, 1500mg
- Soy extract, 3750mg
- Vitamin D, 9000IU

In general, all of the above were well tolerated without side effects. I'd also like to mention I was able to avoid any kind of Edema / Cortisone use during my RT therapy, which I believe may have been at least in part facilitated by Boswellia in combination with Celebrex.


Other:
- Ketogenic diet, max 40 g Carbs per day; generally constant medium to high Ketone bodies when measuring. Started 1 week before RT, and continued to last day
- Caloric restriction, lost ca. 8 kilos in 6.5 weeks of RT, which I think equates approx. 600kcal or so in daily caloric restriction
- Daily morning smoothie, with variety of hopefully beneficial things like berries, broccoli sprouts, spirulina, tumeric powder, Matcha green tea, cocoa powder,  etc.
- Daily walks of ca. 1 hour to combat radiotherapy fatigue and keep fit

Ketogenic diet was somewhat difficult to maintain psychologically, but possible due to my partner's kind help in continuously seeking out new and often tasty dishes to keep things interesting. Caloric restriction much easier, since Temodal anyway caused me lack of appetite. I believe daily walks were very helpful to avoid RT fatigue, which affected me only in very minor way and much less than I expected.

--------------------------------------------------------------

NEXT STEPS & QUESTIONS

I am currently considering next steps, and having talked to various NOs and other Brain Tumor specialists, I am still not entirely convinced what the right way forward is. As expected, most doctors do not want to deviate from the Stupp Protocol (i.e. follow up the RT/TMZ phase with 6 months of 5/23 TMZ cycles). However, I am not convinced such a treatment would necessarily add much benefit in my case, since my tumor is MGMT unmethylated.

One of the leading specialists in Germany told me that the unmethylated MGMT status is irrelevant in the case of IDH1 mutated tumors like mine, since a study (NOA-4) showed that there was no significant difference in responsiveness  between MGMT methylated or unmethylated IDH1 tumors.

https://www.ncbi.nlm.nih.gov/pubmed/19901110

However, upon further research I stumbled across the following interesting study from China, which seems to suggest that IDH1 mutated tumors might in fact be particularly resistant to TMZ (3-10x more resistant in cell culture test). The study also notes that in China they observed relatively little additional benefit of TMZ cycles for the IDH1 mutated group of patients compared to RT alone, and the authors argue that survival benefits for IDH1 mutated tumors may simply be the result of a less invasive / more benign type of tumor relative to wildtype. It makes me wonder if the fact that MGMT doesn't seemingly play as big a role for IDH1 mutated tumors is simply the result of the fact that neither responds well to TMZ...:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4747376/

I'm therefore a bit hesitant to simply go ahead with TMZ therapy hoping for the best, and would like to consider other options.
One approach I am considering is Immunotherapy at the IOZK clinic in Cologne, which is not far from my house. However, because I don't have frozen tumor material, they would have to make a personalized vaccine using a liquid biopsy approach. This, in turn, could make the treatment even more unproven than vaccines anyway are even when made from tumor lysate. An additional option which could possible materialize down the road (but not yet, as no trials are running here presently to my knowledge) is to try to get hold of an IDH1 vaccine on a compassionate use basis.


My immediate next step is to see the MRI results next week, but I'd be very grateful for any advice on how to proceed from here. Especially, I'd like to try and resolve the following questions:

1. Would it be unwise to not do any additional TMZ cycles? Are there any obvious chemotherapy alternatives perhaps?

2. Would the immunotherapy using liquid biopsy at IOZK clinic be a good alternative for ongoing chemotherapy cycles? Would it be advisable to start this right away (i.e. without any additional TMZ cycles), or should I do some TMZ cycles first just to hedge my bets?

3. Any other recommendations in terms of maintenance strategies. E.g. what medication(s) could make a good maintenance therapy, without concurrent chemotherapy?


Thanks in advance for any comments, and wish you all a very happy and most importantly healthy 2018!

Best,
John

Immunotherapy at IOZK Cologne

Hello all,

My 38 year old brother has been diagnosed with a Glioblastoma six weeks ago. Since then he has had total surgical resection and is currently finishing his second week of temodar and radiation. He has also added quite an extensive amount of additional medication as a cocktail approach (I am sure that he will write a more detailed post about the drugs he is taking, when he finds the time). We have found the information in this blog to be extremely helpful. Thanks a lot to Stephen and all of you participating in this great resource.

Right now we are thinking about additional options for the time after his chemo/radiation phase. One thing that we are quite interested in is immunotherapy. Unfortunately my brother’s resected tumor tissue hasn’t been frozen but conserved in paraffin so that options are somewhat limited. We have contacted IOZK in cologne and they have said that they could produce a vaccine without the tumor tissue, using only a blood sample. Cologne is not too far from where we live.

I have read various comments, in this blog, about the IOZK clinic and I know that some of you have been, or have had family members being treated there. I would be very grateful if you could tell me about your experience with the clinic and whether you would recommend giving it a try.

Thanks!

Phil

Immunotherapy and cannabis

Hi,

Does anyone have information on concurrent use of immunotherapy and cannabis? I read that cannabis can have anti-inflammatory effects primarily due to it suppressing the immune system. This seems worrisome if the patient is on immunotherapy. All I could find is one retrospective study on cannabis and opdivo use: http://oncologypro.esmo.org/Meeting-Resources/ESMO-2017-Congress/The-effect-of-cannabis-use-on-tumor-response-to-Nivolumab-in-patients-with-advanced-malignancies

Has anyone's doctor mentioned a possible contraindication?

Thank you.

Trivalent CAR T-cells

This study, called Trivalent CAR T-cells Overcome Interpatient Antigenic Variability in Glioblastoma, just appeared as an accepted manuscript in Neuro-Oncology.  See abstract here.

This was a preclinical study tested in mice, but is an exciting development, as this CAR T-cell cocktail approach is more likely to be effective than CAR T-cells targeted to a single antigen.

I'll upload the full study to the Library (Immunology and Immunotherapy folder, in a new CAR T-cell subfolder).

Navigating the Brain Tumor Maze with Professor Rajiv Khanna

This will be particularly interesting for patients in Australia and much of the discussion is about CMV-directed T-cell therapy being developed there in Brisbane.  The discussion turns to GBM at minute 25:25 of the podcast.  Click here for the link.

(Arabinoxylan) Rice Bran improves natural killer white cell activity

Came across this, which is an lengthy advertisement but well cited about how enzymatically modified rice bran (EMRB)/Arabinoxylan substantially increases the cytotoxicity of natural killer white cells.

http://www.lifeextension.com/magazine/2015/1/activate-your-natural-killer-cells/page-01

Here's the NCBI abstract:
https://www.ncbi.nlm.nih.gov/pubmed/25541298

My question is this: If someone is taking a PD-1 inhibitor, would it make sense to also supplement with this or is it akin to putting gas on a fire?

Thoughts?

From Musella's website: Immunotherapies for GBM: Tumor Vaccines by Linda Liau, M.D., Ph.D., M.B.A.

Immunotherapies for GBM: Tumor Vaccines by Linda Liau, M.D., Ph.D., M.B.A.         This is a video about the DCVax trial, given by one of my all time favorite brain tumor doctors, Dr. Liau.  This looks very promising. We are hoping to hear the results of the big phase 3 trial soon.  In the earlier trials and in the early progressors which were excluded from this trial but were followed as they took the vaccine,  about 25% of the patients went on to be long term survivors, with many alive and progression free 5-10 years later.  That is unheard of with the standard treatments. Some other immunotherapies have also reported similiar results (although not as long follow up).    We are hoping this large phase 3 trial shows something close to that so it can be approved quickly and all patients can benefit from it.  Best of all it had no serious side effects. Dr. Liau is on the Musella Foundation Medical Advisory Board.  The Musella Foundation has supported Dr Liau's immunotherapy research with $375,000 in grants and we have never received any financial  support from the company developing this treatment, Northwest Biotherapeutics.

Brain Research Institute

I found this link on ABTA and thought it was helpful. 

http://www.cancerresearch.org/cancer-immunotherapy/impacting-all-cancers/brain-cancer

Triple combination of dual checkpoint blockade + radiosurgery -> 100% mouse survival

http://clincancerres.aacrjournals.org/content/early/2016/12/04/1078-0432.CCR-15-1535.long

I don't recall seeing a mouse study this successful before.  This study utilized the orthotopic, syngeneic GL-261 mouse glioma model.  Triple combination of PD-1 antibody, TIM-3 antibody, and stereotactic radiosurgery led to 100% mouse survival at day 100, while all untreated control mice were dead by day 30.  Furthermore, the "cured" mice were completely resistant to new tumor formation when re-challenged with glioma cells.  I'll upload this study to the Library, in the Immunology and Immunotherapy folder, Checkpoint inhibitor subfolder.

Phase 1/2 trial in Japan: dendritic cell + glioma cell fusion immunotherapy

https://www.ncbi.nlm.nih.gov/pubmed/27688162  (the full study will be added to the Immunotherapy folder of the Library)

This trial recruited 22 newly diagnosed and 10 recurrent GBM patients.  The therapy consisted of autologous glioma cells (lethally irradiated) chemically fused with autologous dendritic cells.  The fusion cells were also transfected with poly I:C (a synthetic double-stranded RNA analog) and small interfering RNA for IL-10 (IL-10 is an immunosuppressive cytokine).  For the newly diagnosed patients this treatment was added onto standard treatments (radiation and temozolomide).

Median progression-free survival (PFS) and overall survival (OS) for the 22 newly diagnosed patients was 17 and 30 months.  Average age of these patients was 56.7 years.

Median PFS and OS (from recurrence) for the 10 recurrent GBM patients was 11 and 17 months. Average age was 50.1 years.

This is certainly one of the best phase 2 outcomes for newly diagnosed GBM yet published in a peer-reviewed journal, and the results for recurrent GBM are also impressive (though only 10 recurrent patients were treated and the average age was on the low side).

Resveratrol and curcumin suppress immune response through CD28/CTLA-4 and CD80 co-stimulatory pathway

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1810449/

Low Dose Naltrexone

http://astrocytomaoptions.com/re-educating-the-immune-system/

As mentioned above, one of the main endogenous opioids with increased production following low dose naltrexone is met-enkephalin (also known as methionine enkephalin, and as opioid growth factor). A Chinese study published online in August 2016 examined the effects of met-enkephalin on microglial cells in culture [46]. As explained in this study and elsewhere, microglia (the resident macrophages of the nervous system) and macrophages infiltrating from the systemic circulation are actively recruited into tumors, polarized to a tumor-promoting M2 phenotype and away from a tumor-fighting M1 phenotype, and can make up as much as 30% of a GBM tumor. The investigators found that at the optimal concentration of met-enkephalin (1 picomolar), M1-type cytokine production and surface proteins were increased in the microglia, including interleukin-12, TNF-alpha, CD86, CD40, and iNOS. In contrast, M2 cytokines and markers were not affected, including interleukin-10, TGF-beta, CD163, and arginase. Phagocytosis (a main function of M1 macrophages) and cytotoxicity towards U87 glioblastoma cells was increased by met-enkephalin treatment. Thus, met-enkephalin (opioid growth factor), an endogenous opioid whose production is increased in humans following transient opioid receptor blockade by low dose naltrexone, may aid glioma patients by reverting tumor-associated microglia to an M1 anti-tumor phenotype.

View common questions and answers about the use of low dose naltrexone at LDN Science. Especially interesting areinterviews with Dr. Ian Zagon, who discovered the clinical benefits of naltrexone in very low doses.

The effective dose of low dose naltrexone ranges from 2.5 – 10 mg, with the most common dose being 4.5 mg daily. LDN may be taken in the morning or evening. Some individuals may experience sleep disturbances (such as nightmares) caused by LDN and these people may choose to take their daily dose in the morning.

Optimising cancer immunotherapy

Interesting information on immunotherapy

http://emjreviews.com/wp-content/uploads/Optimising-Cancer-Immunotherapy-Challenges-and-Opportunities.pdf

Prioritization schema for immunotherapy clinical trials in glioblastoma

This looks like an important paper by a number of heavyweights in neuro-oncology, though I haven't read through it yet.

Abstract

I will upload it to the Library (folder 3, Immunology and Immunotherapy) now.

DC vaccine plus PD-1 antibody in GL261 mouse model

A nod to the anonymous commenter who posted a link to this study in the Dendritic Cell Therapy?thread.  This study is the subject matter for my latest update on Astrocytoma Options.

http://astrocytomaoptions.com/immunotherapy/

PD-1 ANTIBODIES (NIVOLUMAB AND PEMBROLIZUMAB)

Late in 2014, the FDA approved two novel drugs for metastatic melanoma. These two drugs, pembrolizumab (Keytruda) and nivolumab (Opdivo) are both antibodies against PD-1, an immune checkpoint found on the surface of immune cells, that leads to anergy (deactivation) or death of immune effector cells when in contact with PD-L1 (ligand for PD-1) expressed on other cells. Though the PD-1/PD-L1 immune checkpoint system evolved as an important means to prevent autoimmunity conditions, the system is clearly co-opted by tumors to escape targeting by host immune cells. As of this writing in July 2016, there are no less than 13 trials currently recruiting glioblastoma patients for therapy involving nivolumab or pembrolizumab, and one trial testing a novel PD-L1 antibody (MEDI4736). The first trial for high grade gliomas to combine a dendritic cell vaccine with a PD-1 antibody is the AVERT trial at Duke University, which opened in early 2016 (NCT02529072). A second trial called CAPTIVE, opened in June 2016, combines the DNX-2401 adenovirus with pembrolizumab (NCT02798406). These two trials are likely the leading edge of the future of immunotherapy: combination of vaccine or oncolytic virotherapy with immune checkpoint blockade.

Preclinical evidence supporting this combination in high grade glioma comes in the form of a study published online in July 2016, by a team of UCLA researchers [1]. In this study, mice were treated with subcutaneous injections of a lysate-pulsed dendritic cell vaccine prepared from murine progenitor bone marrow cells and GL261 mouse glioma cell lysate. Mice were treated with vaccines at either the first day of intracranial GL261 glioma implantation, or at day 3 after tumors were established. Dendritic cell (DC) vaccination significantly increased survival times only in the group receiving early vaccination. In contrast, no prolongation of survival was seen in mice receiving later vaccination, in spite of tumor infiltration by glioma-reactive CD3+ lymphocytes in these mice.

PD-1 was increased on tumor-infiltrating lymphocytes in both untreated and DC vaccinated mice compared to splenic lymphocytes, indicating a localized immunosuppression in the tumor environment. Following DC vaccination, PD-1 was the only marker of immune inhibition increased in the tumor-infiltrating lymphocyte population. All other markers examined, including CTLA-4 (target of the drug ipilimumab) and TGF-beta, were downregulated following vaccination.

These observations led the researchers to treat mice with established gliomas with the combination of DC vaccination plus PD-1 monoclonal antibody (similar in function to the FDA-approved antibodies nivolumab and pembrolizumab). Remarkably, while no survival benefit was observed in mice treated with either vaccine or PD-1 antibody alone, 40% of mice treated with the combination survived at least to day 60 (none of the mice in the other arms survived to day 40).

The survival benefit of the combined therapy was found to be completely dependent on CD8+ cytotoxic T-lymphocytes, as depletion of these cells in the mice wiped out any benefit of treatment. Though mice in both DC vaccine treated, and DC vaccine plus PD-1 antibody treated groups had increased infiltration of CD8+ lymphocytes into their tumors, only combination treated mice had increased proportions of activated CD8+ CD25+ T-cells, showing that PD-1 antibody in addition to DC vaccine was necessary to maintain an activated population of CD8+ T-cells in the tumor environment.

Combination treatment also increased populations of tumor-infiltrating memory T-cells, and when surviving mice from the combination treatment group were re-challenged with a second injection of GL261 glioma cells in the contralateral brain hemisphere at day 60, they again survived significantly longer than untreated controls, though they had no additional treatments beyond the initial treatment at the time of the first tumor cell injections.

GBM samples taken from clinical trial patients before and after treatment with DC vaccines at UCLA showed both abundant expression of PD-L1 (the ligand for PD-1) in the tumor environment, as well as increased PD-1 expression on CD8+ tumor-infiltrating lymphocytes following dendritic cell vaccination. This demonstrates that, as seen in mice, PD-1 expression is a mechanism of immunosuppression following DC vaccination in human patients, a means of tumor resistance to the treatment.

Ex vivo, tumor-infiltrating lymphocytes taken from GBM patients undergoing resection showed greatly increased cytotoxicity against tumor cells when PD-1 antibody was added to the co-culture.

Significance: this study clearly shows that tumor lysate-pulsed dendritic cell vaccination is not sufficient to increase survival in mice with established gliomas, and that additional reversal of local immunosuppression with PD-1 antibody is also required. Human GBM tissue showed the same increase in PD-1 expression following dendritic cell vaccination, as a means of tumor resistance to treatment. Pending demonstration of the safety of combining dendritic cell vaccinations with PD-1 antibodies in current trials for high grade glioma, future vaccine trials should logically include such antibodies (eg. nivolumab or pembrolizumab), especially for patients with significant residual tumor post-resection. This combination treatment is likely necessary to bring the benefits of anti-tumor vaccines to a patient population that otherwise might not significantly benefit – those with significant residual tumor burden.

1. PD-1 blockade enhances the vaccination-induced immune response in glioma. Antonios et al. 2016.
   READ SOURCE DOCUMENT

Checkpoint blockade and Cox 2 inhibitors

Since it is becoming increasingly evident that inflammation can be beneficial to enhanced immune response when using checkpoint inhibitors, I am wondering if it might be prudent to discontinue celebrex and possibly even EFA's (fish oil in this case), in an attempt to enhance the immune response.  Any thoughts on this?

Dendritic Cell Therapy?

Has anyone has success with DC therapy here in the states?

We are looking at Dr. Chang's offering here:
https://dendritic.info/

And the Issel's center here:
http://www.issels.com/

For Dr. Chang's offering, does one need to travel to Germany initially or can it all be done here? I know that his NCV offering requires travel to Germany, initially.

Anyone have any experience with either Chang or Issel for GBM?