The IOZK clinic in July 2018 published an article with information on the treatment of 15 patients.
Some of the details seemed interesting to me.
The first 10 patients (in the table) were treated using vaccines based on dendritic cells:
- Of these, 3 patients survived 18, 22 and 10 months. By the way, the patient, who survived 18 months, used the CUSP9 protocol.
- The remaining 7 patients continue treatment. However, of these 7 patients with no progression, only 2, with a result of 27 and 17 months without progression after surgery. In others, the tumor slowly progresses.
Also, we see that 3 patients out of 15 used perillol alcohol (POH).
http://www.iozk.de/aktuelles/iozk_glioblastoma_immunotherapy_austin_oncology_report_2018.pdf
"The median PFS was 13 months. Median OS was not reached with a median follow up of 17
months (rang 4-30 months). Estimated overall survival at 30 months was 58%..."
"DC vaccinations have been given after the chemotherapy. The obvious reason is that temozolomide might affect T cell proliferation and hence the anti-tumoral immune response upon DC vaccination."
Does this mean that it is better not to combine the Stupp protocol with the DC vaccine in the same period?
Some of the details seemed interesting to me.
The first 10 patients (in the table) were treated using vaccines based on dendritic cells:
- Of these, 3 patients survived 18, 22 and 10 months. By the way, the patient, who survived 18 months, used the CUSP9 protocol.
- The remaining 7 patients continue treatment. However, of these 7 patients with no progression, only 2, with a result of 27 and 17 months without progression after surgery. In others, the tumor slowly progresses.
Also, we see that 3 patients out of 15 used perillol alcohol (POH).
http://www.iozk.de/aktuelles/iozk_glioblastoma_immunotherapy_austin_oncology_report_2018.pdf
"The median PFS was 13 months. Median OS was not reached with a median follow up of 17
months (rang 4-30 months). Estimated overall survival at 30 months was 58%..."
"DC vaccinations have been given after the chemotherapy. The obvious reason is that temozolomide might affect T cell proliferation and hence the anti-tumoral immune response upon DC vaccination."
Does this mean that it is better not to combine the Stupp protocol with the DC vaccine in the same period?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889286/
ReplyDelete"DC vaccination induced a significant, persistent activation of NK cells, whose increased response was significantly associated with prolonged survival. CD8+ T cells underwent rapid expansion and priming but, after the first administration of adjuvant TMZ, failed to generate a memory status."
"The negative effect of TMZ on the formation of T cell-associated antitumor memory deserves consideration in future clinical trials including immunotherapy."
In answer to your question, I would say possibly. If the patient has a tumor that will be responsive to vaccine treatment, it would probably be best to apply the vaccine before chemotherapy begins, and reserve chemotherapy until later as a salvage therapy.
On the other hand if the tumor is one that will not respond to the vaccine treatment, it would be better to apply chemotherapy upfront.
Obviously, it's difficult to predict beforehand which tumor will or won't respond to vaccine. We don't yet have well established immune biomarkers that would allow such a prediction, but we are moving closer to that and may get there before too long.
Thank you very much for the detailed answer!
DeleteDo you have any thoughts on enhancing the effect of the DC-vaccines?
My mom has just started a course of DC-vaccines based on the remains of other people's tumors (since our tumor was not frozen)
Does this study also mean that it is possible to try using DC-vaccines after chemotherapy courses with temozolomide?
DeleteIt's possible, but it might take some time for the full recovery of memory T-cell responses. But the Italian study in OncoImmunology also showed a natural killer cell associated benefit to vaccination, even with impaired memory T-cell response.
DeleteBy the way, in the study of DCVax-L vaccines patients received vaccines based on dendritic cells simultaneously with temozolomide. Nevertheless, the trial was completed successfully.
Deletehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975654/
"Patients in both arms continued to receive monthly adjuvant temozolomide (150–200 mg/m2/day × 5 days every 28 days), interspersed with the DC vaccine or placebo treatments administered on Days 0, 10 and 20, then Months 2, 4 and 8, and thereafter at 6-month intervals starting at month 12."
This protocol also says that vaccines based on dendritic cells will be administered together with standard chemotherapy.
DeleteA randomized controlled phase II trial of vaccination with lysate-loaded, mature dendritic cells integrated into standard radiochemotherapy of newly diagnosed glioblastoma (GlioVax): study protocol for a randomized controlled trial.
2018 https://www.ncbi.nlm.nih.gov/pubmed/29801515
"Patients in the vaccination arm receive 4 priming vaccinations and 3 boosting vaccinations with tumor-lysate-loaded, mature DC as add-on therapy to the standard therapy, between radiochemotherapy and adjuvant TMZ and in the first 3 cycles of adjuvant TMZ, respectively."
In this trial, dose-intensified TMZ was used with vaccines. Controversial conclusions about the effect of temozolomide.
Delete2017 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559300/
"Our study suggests that DI-TMZ (dose-intensified) is more efficacious if used in concert with antigen-specific vaccination for GBM...
All 11 patients received at least seven vaccines of pp65-DCs. The kinetics of pp65 vaccine responses showed a significant decline at Vaccine-4. This diminished response may have been a result of 1) natural contraction in pp65 reactivity following a one month latency between Vaccine-3 and Vaccine-4 or 2) a possible detrimental effect of DI-TMZ cycle 2 depleting pp65-specific effector T-cells. Following Vaccine-5, when monthly DI-TMZ and monthly pp65-DCs were administered, we observed a slight upward trend in mean pp65 reactivity at Vaccine-7, mostly driven by increases in five of the 11 patients."
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My mom now received 6 weekly vaccines based on other people's tumors. Since our tumor was not frozen.
I think it's probably better to delay the next cycle of TMZ + CCNU and continue the vaccine? The effect on the MRI is not yet visible, the tumor stands still. I'm afraid that the next dose of temozolomide will negatively affect the possible effect of vaccines.
Dear all
DeleteThank you for this discussion which is very important.
The integration of immunotherapy within the standard Stupp-based treatment is a focus of interest for me since 2006. We published the HGG-2006 study based on a schedule where 4 DC vaccinations were given after the radiochemotherapy, and where boost vaccines were given during the maintenance TMZ 5-day cycles. The rationale can be found in the publications from Ardon et al. This schedule is taken over by my friends Michael Sabel and Rüdiger Sorg for the GlioVax study.
In building up my experiences over the time, I however see that TMZm can affect the T cell proliferations. These are the real immune cells that we aim to have. The more you stimulate T cells, the more they proliferate and the more they are sensitive to chemotherapy like TMZm. On top of that, we have now other ways to strengthen the antitumoral actions during the TMZm, namely by adding the oncolytic virus and the hyperthermia. That is the reason why we placed now the full vaccines at the end of the TMZm, to keep the maximum immune effectivity, without chemotherapy. Oncolytic virus NDV and hyperthermia kill tumor cells via immunogenic cell death mechanisms while TMZm kills tumor cells via genetic mechanisms. The rationale of this combination is further described in the paper.
Dose intense TMZ or metronomic TMZ really deplete T cells which we aim to stimulate, so I do not understand the rationale of such approach. Indeed the study of Liau with DCVax-L was finished successfully, but the randomized arm versus placebo is not yet demonstrated (at least not published as far as I know). So we have to wait to see the experience and the effectiveness of this combination. The pp65-DC showed "a slight upward trend in mean pp65 reactivity at Vaccine-7" hence demonstrating that dose-intense TMZ might hamper the immune reactivity.
I hope that this comment is of help. At least it shows that combinations are mandatory but not easy to design for obtaining the best possible effect.
Thank you for sharing your experience and observations. I was personally impressed by the Italian study showing that combined with TMZ, vaccines can still give a benefit associated with natural killer cells, but the administration of adjuvant TMZ cycles very much harmed memory T-cell responses. "Another constraint to the development of CD8+ T cell antitumor activity and memory is likely due to their exquisite sensitivity to TMZ. We found that administration of adjuvant TMZ exerts negative effects on CD8+ T cell activation and in particular on the generation of immune memory and central memory"
Deletehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889286/
I know it will be difficult for clinical trials to withhold/delay conventional treatments for the sake of a more experimental therapy. I do believe the vaccines have shown efficacy even when combined with monthly TMZ, but I wonder how much more effective they could have been if monthly TMZ cycles had been delayed in order to allow for the development of maximum CD8+ T-cell proliferation and immune memory following vaccinations.
I agree, clinical trial design will be tricky to obtain the best possible outcomes.
Perhaps lomustine does not have the same negative effect as temozolomide?
DeleteLomustine has a similar toxicity profile to temozolomide, with myelosuppression (lowered white blood cell counts, including lymphocytes {T cells, B cells}, and lowered platelet counts) usually being dose-limiting.
DeleteWith great difficulty, I bought the antigen CMV pp65. Our microbiologist will try to make vaccines based on dendritic cells, aimed at CMV pp65.
DeleteI think to use the next cycle of CCNU + TMZ and these vaccines immediately after it.
CCNU + TMZ will lead to severe lymphopenia. However, as the authors of the study (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5559300/) indicate, vaccines after lymphopenia can lead to a reprogramming of the immune system.
https://www.aacr.org/Newsroom/Pages/News-Release-Detail.aspx?ItemID=1047
DeletePrevious work had shown that TMZ generates profound lymphopenia or the loss of immune cells, which offers a unique opportunity to retrain the immune system, Batich explained. The researchers administered dose-intensified temozolomide (TMZ) as a strategy to further enhance the immune response.
“The dose-intensified temozolomide induces a strong state of lymphopenia,” said Batich. “With that comes an opportune moment to introduce an antigen-specific vaccine, which redirects the immune system to put all hands on deck and fight that target.”
The difficulty is that my mom also takes a combination of chloroquine + sirolimus (2 mg per day). There are many studies on the negative effect of sirolimus on dendritic cells of patients.
DeleteFor example:
2017 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806813/
"These date indicate that the immunological effects of everolimus affect multiple immune cell subsets and altogether tip the balance in favor of immunosuppression, which can be considered a detrimental effect in the treatment of cancer"
I would consider stopping everolimus while doing immunotherapy.
Delete