Approaches Based on Immunotherapy to Fight Glioblastoma Multiforme
Here we are at the eleventh episode of the Ben Williams guide translation project on treatment options for Glioblastoma Multiforme. This is the first part of chapter 8 of the guide which I have divided into two parts. In the first part we talk about immunotherapy and in particular about vaccines, personalized vaccines with dendritic cells, tumor-associated antigen vaccines and the famous vaccine targeted at CytoMegaloVirus (CMV). The advice is still to use this information to discuss it with the medical team that is following you. You can also point them to the references to supporting scientific works.
I ask you once again if possible to help the fundraising campaign Glioblastoma.it for CUSP-ND for Emanuele at least by sharing the link in order to spread the word and raise awareness in as many people as possible. Enjoy the reading!
Since cancer cells have a different genetic structure from normal cells, they generate foreign proteins which in principle should be detected by the immune system and cause the same type of immune reaction as any foreign virus or bacterium. This basic fact suggests that boosting one’s immune system could be an effective approach to cancer treatment. Such an approach has an immediate appeal because it is certainly preferable to strengthen the immune system rather than poison the entire body in the hope that the cancer cells will be killed before the body runs out of its vital resources. As attractive as this philosophy may be, translating it into effective cancer treatment has proven extraordinarily difficult. Contrary to popular belief, immunological treatments are not without side effects. Interferon treatment has very defined debilitating effects, as do cytokines such as interleukin-2 and tumor necrosis factor, because their modus operandi is essentially to create an inflammatory immune reaction not unlike a severe allergic reaction. When this inflammatory process is too high, it can even be fatal.
The Holy Grail of immunological approaches to cancer treatment is the development of effective vaccines. In principle this should be possible due to differences in the protein structure of cancer cells from normal cells. But two general problems need to be overcome. The first is that different individuals have tumors with different groups of antigens (proteins), so generic vaccines are unlikely to be effective; therefore specific vaccines are needed for the single patient. The second problem is that the immune system is not an efficient detector of tumor antigens. In part this is due to the enzymes the tumor secretes which in effect provide a protective coat that prevents detection. The larger the tumor, the stronger its defense mechanisms are to counteract detection by the immune system. This is one of the reasons why most vaccines work best when there is a minimum of tumor burden.
DCVax and other lysate pulsed dendritic cell vaccines
Methods to improve the detection of tumor antigens are now the subject of intense research for various types of cancer. The most successful approach to date involves the use of dendritic cells, which have been characterized as “professional antigen presenting cells”. Dendritic cells are extracted from the blood, then co-cultured with a lysate prepared from the patient’s tumor cells and stimulated with granulocyte macrophage colony stimulating factor (GM-CSF) and interleukin-4 (GM-CSF is the growth factor used to counteract the decrease in white blood cell count due to chemotherapy). This growth factor also causes the mixture of cancer and dendritic cells to expand. This mixture is then injected into the patient, causing an increased reaction from the immune system.
This use of dendritic cells has been applied to different types of cancer. Its use on brain cancer was pioneered by Dr. Keith Black and his team at UCLA, then continued at Cedars Sinai when Dr. Black’s team moved to that institution. A parallel program at UCLA was continued by Dr. Linda Liau. Other centers using this approach are present in Belgium, China and Japan. In one of the first small clinical trials (149), nine new high-grade glioma patients received three separate vaccinations two weeks apart. Robust T cell infiltration was detected in tumor samples and median survival was 455 days (compared with 257 days in the control population). A subsequent report (150) involving 8 patients with GBM produced a median survival time of 133 weeks, compared with a median survival of 30 weeks for a comparable group of patients who received other treatment protocols. At two years, 44% of patients were progression-free, compared to only 11% of patients treated with the Stupp protocol. An excellent review of the clinical findings and technical issues associated with vaccine studies is provided by Wheeler and Black (151).
In the largest of the clinical trials (152), 34 GBM patients (23 with recurrent tumors, 11 newly diagnosed) were evaluated for their immunological response to the vaccine using interferon production as a measure, with the result that only the 50% of the patients showed a response. The degree of response was moderately related to survival time: 642 days for responders, 430 days for non-responders. Five of the 34 patients were alive at the time of intercourse, with survival times ranging from 910 to 1216 days, all classified as immunological responders. It should be noted that the mean age of the patients in this study was 52 years, only slightly lower than the typical GBM population, while many of the other vaccine studies mainly included younger patients.
Among the most promising results of pulsed dendritic cell lysate vaccines is the UCLA research program led by Dr. Liau. In the more detailed report of the results (153) 15 newly diagnosed GBM patients and 8 patients with recurrent tumors (mean age = 51), received the vaccine an initial dose of dendritic vaccine followed by three booster vaccines in combination with POLY ICLC or imiquimod applied locally to the injection site. For all patients, the median time to progression was 15.9 months. Median survival time for newly diagnosed patients was 35.9 months, and 2- and 3-year survival rates were 77% and 58%. For relapsing patients, the median survival from the time of initial enrollment in the trial was 17.9 months. Subsequent reports have come from press releases from Northwest Biotherapeutics, the biotech company that sponsors the DCVax studies. A large multicenter Phase III study is currently underway.
As of July 2015, no results from the phase 3 DCVax-L study were made public, although the outcomes of patients from an “information arm” who received DCVax-L were published by Northwest Biotherapeutics in March (see press release ). This information arm consisted of 51 patients who enrolled in the phase 3 study but were then excluded from the study due to their early disease progression prior to the first vaccination. Patients received DCVax injections and were then followed up for outcomes.
The survival results in this group are summarized in a Youtube video with Marnix Bosch, the company’s Chief Technical Officer. Within this group of 51 patients, a subgroup of 25 patients cons “indeterminate” iderates, meaning that they had evidence of disease progression at the baseline visit (which made them ineligible to participate in the study), but subsequently had stable disease, modest progression or modest regression. This group of patients had a median survival of 21.5 months. As of March 2015, nine of these patients were still alive after 24 months of follow-up, six of these nine were alive after 30 months of follow-up, and four of these nine were alive between 35 and over 40 months. Therefore, we can expect the median survival of the phase 3 study (patients with no disease progression at baseline) to be at least greater than 21.5 months.
Agenus Prophage vaccine (heat shock-96 protein peptide complex)
A variation in the use of dendritic cells consists in having first subjected the tumor tissue to a heat shock treatment to increase the expression of heat shock proteins, which are then extracted from the blood and incubated with dendritic cells of individual patients. In a clinical study (163) conducted at UCSF and Columbia for patients with heavily pretreated recurrent tumors, the vaccine produced a median survival of 42.6 weeks (approximately 9.8 months), which compares favorably with the survival time of 6 months of historical data, and is comparable to 9-11 months of Avastin which is used on patients with recurrent tumors.
A subsequent press release from Agenus, Inc, a biotech company sponsoring the research, reported the results of the phase II clinical trial in which the dendritic heat shock vaccine was combined with the standard Stupp protocol (164). Median progression-free survival was 17.8 months and median survival was 23.8 months. This median progression-free survival of 17.8 months is perhaps the longest PFS ever seen in a substantial-sized Phase 2 study for newly diagnosed glioblastoma.
Follow-up data (reference 339, 2011 report) presented at the 2015 ASCO conference revealed that patients with high expression of PD-L1 (the ligand for the immune cell surface PD-1 checkpoint that is the target of therapeutic antibodies nivolumab and pembrolizumab) had a median survival of 18 months, while those with low PD-L1 expression had a median survival of 44.7 months. This finding suggests that the efficacy of the heat shock protein peptide vaccine could be significantly improved with the co-administration of PD-1 antibodies such as nivolumab or pembrolizumab.
Tumor-associated antigen vaccines
A disadvantage of the DCVax approach is that it requires brain tissue to be extracted from individual patients to produce the vaccine. An alternative approach was used by Dr. Black’s team at Cedars Sinai. Dendritic cells are still taken from the peripheral blood of individual patients, but instead of mixing tumor tissue lysate with those cells, a collection of six typical GBM proteins are mixed with the dendritic cells, creating an immune response to those antigens, and the mixture is then returned to the patient through vaccinations. In a phase I study (158), 20 GBM patients (17 newly diagnosed, 3 with recurrent cancers) received three vaccinations two weeks apart. Median PFS was 16.9 months and median overall survival was 38 months. At the time of the clinical trial report, six of the patients had shown no signs of cancer recurrence. A subsequent follow-up was reported in a press release from ImmunoCellular Therapeutics (159), the biotech company that sponsors the vaccine (now called ICT-107). The three-year survival rate was 55%, with 38% of patients showing no signs of recurrence.
The update on the clinical trial (160), presented at the 2013 meeting of the World Federation of Neuro-oncology, reported that 7 of the 16 original patients in the study were still alive, with survivors ranging between 60 and 83 months. Another patient who was still cancer-free after five years died of leukemia.
A phase II randomized trial is currently underway, with interim results recently reported by ImmunoCellular Therapeutics (161). Despite the impressive results described above, there was no statistically significant difference in median survival between the vaccinated group and that treated with a placebo, although there was an advantage of 2-3 months for the group that received the vaccine. However, a similar difference in progression-free survival was statistically significant. The company pointed out that the results were preliminary and that they expected the difference in progression-free survival to translate into differences in overall survival with longer follow-up.
The updated data from the phase II ICT-107 study were presented in June 2014 at the ASCO annual meeting (309). An important conclusion to be drawn from the new data is that patients positive for HLA-A2 (a variant of the human leukocyte antigen-A gene) appear to benefit significantly from the vaccine. HLAs are proteins that present the antigen found on the cell surface. HLA-A2 is the most common variant in North America and Europe according to the press release and this group comprised 62% of patients randomly entered in this study. The updated results were presented only for HLA-A2 positive patients, with results further broken down by MGMT methylation status.
Survival outcomes in this study are measured from the time of randomization following chemoradiotherapy and the average time between initial surgery and randomization was 83 days (2.7 months).
For HLA-A2 positive patients with unmethylated MGMT, the ICT-107 vaccinated group had a median survival advantage of 4 months over the placebo group. The ICT-107 group also had a median advantage of 4.5 months in progression-free survival. These advantages in the vaccine-treated group did not reach statistical significance, although this is perhaps due to the small number of patients included within these subgroups. 21% of patients treated with ICT-107 were still alive at the time of analysis, compared with only 7% of patients treated with placebo.
Median survival has not yet been achieved in the HLA-A2 positive, methylated MGMT group, although treatment with ICT-107 in this subgroup resulted in a significant and statistically significant increase in median progression-free survival: 24.1 months versus 8.5 months of the placebo group. This huge improvement in median progression-free survival in this subgroup is likely to translate into a significant median improvement in overall survival.
Unfortunately, in June 2017, Immunocellular Therapeutics announced that the Phase 3 ICT-107 trial was suspending recruitment due to insufficient funding. In the press release it was stated that the company was looking for a partner for the collaboration or the acquisition of its ICT-107 Program and that it was also taking measures to ensure follow-up of patients already participating in the study.
A similar approach was used by Dr. Hideho Okada and colleagues at the University of Pittsburgh. In a pilot study using this approach with patients on recurrent tumors (162) several important tumor responses were observed. Median survival for the 13 GBM patients in the study was 12 months, with many of the patients still progression-free at the time of intercourse. A later version of this therapy, called SL-701, consists of three shortened peptides corresponding to glioma-associated antigens and is now being tested in a Phase I / II study for HLA-A2 positive recurrent glioblastoma (NCT02078648 ).
Cytomegalovirus (CMV) targeted dendritic cell vaccine
This approach is based on the discovery that most GBM tumors are infected with cytomegalovirus, a common herpes virus. GBMs have a high incidence of the virus present (according to some estimates over 90%) while normal brain cells do not. The new therapeutic approach involves targeting a specific protein component of the CMV virus, which then kills the virus and the host cell.
The results of a small study for Duke’s anti-CMV dendritic cell vaccine with or without preconditioning with an injection of tetanus / diphtheria toxoid were published in Nature in March 2015 (320). There were 6 patients with newly diagnosed glioblastoma in each arm. In the 6 patients treated with the vaccine but without preconditioning for tetanus / diphtheria, the median progression-free diagnosis and overall survival was 10.8 and 18.5, not significantly better than historical controls. In the group of patients who received injection site preconditioning with tetanus / diphtheria, three of the patients were alive with no disease progression at 44-47 months after diagnosis. A Wall Street Journal article published at the same time as the study itself published Nature provided updated information, revealing that two of these long-term survivors died nearly 5 and 6 years after diagnosis, while the remaining patient was still alive at over 8 years. years from diagnosis. An update presented at the 2016 AANS Conference revealed that this patient was still alive and without tumor recurrence at 120 months (10 years). The purpose of the tetanus / diphtheria booster is to improve the migration of dendritic cells to the lymph nodes. Given the surprising success of the anti-CMV dendritic cell vaccine combined with a tetanus / diphtheria booster injection, a phase 2 randomized trial was opened in 2015 with an arm that will receive tetanus / diphtheria toxoid preconditioning and other arm that will receive saline (essentially placebo). Both arms will receive the anti-CMV dendritic cell vaccine (NCT02366728).
A second phase II single-arm study (ATTAC-GM) combined intense dose temozolomide (100 mg / m2 for 21 days of a 28-day cycle) with CMV dendritic cell vaccine and tetanus preconditioning. Median progression-free and overall survival for the 11 patients was 25.3 and 41.1 months. These data were presented at the 2016 AANS annual meeting by Kristen Batich.
A separate trial (NCT00626483) at Duke for newly diagnosed glioblastoma is testing the CMV-targeted dendritic cell vaccine in combination with basiliximab, a CD25 antibody intended to inhibit the regulatory T cell (Treg) population. In a report published at the 2015 ASCO meeting, it is revealed that in a pilot study of seven patients treated with this combination therapy, the median progression-free survival and overall survival were 23.5 and 30.3 months, respectively.
Currently recruiting clinical trials to test vaccines against CMV pp65 with or without tetanus / diphtheria preconditioning or basiliximab includes the ELEVATE trial at Duke University (NCT02366728), the PERFORMANCE trial also at Duke (NCT02864368), the ATTAC-II trial from the University of Florida (NCT02465268) and the AVERT study for Grade III and GBM recurrent gliomas at Duke University (NCT02529072).
(149) Yu, J. S., et al. Vaccination of malignant glioma patients with peptide-pulsed dendritic cells elicits systemic cytotoxicity and intracranial T-cell infiltration. Cancer Research, 2001, 61, 842-847.
(150) Yu, J. S., et al. Vaccination with tumor lysate-pulsed dendritic cells elicits antigen-specific, cytotoxic T cells in patients with malignant glioma. Cancer Research, 2004, 64, 4973-4979.
(151) Wheeler, C. J., & Black, K. L. DCVax-Brain and DC vaccines in the treatment of GBM. Expert Opin. Investig. Drugs, 2009, 118(4), 509-519.
(152) Wheeler, C. J., et al. Vaccination elicits correlated immune and clinical responses in glioblastoma multiforme patients. Cancer Res., 2008, 68 (14), 5955-64.
(153) Prins, R. M., Soto, H., Konkankit, V., et al. Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clinical Cancer Research, 2011, 17(6)., 1603-15.
(158) Phuphanich, S., Wheeler, C. J., Rudnick, J. D., et al. Phase I trial of multi119epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunology and Immunotherapy, 2013, 62, 125-135.
(159) Press Release from ImmunoCellular Therapeutics, Sept 12, 2011
(160) Phuphanich, S., et al. Long-term remission over 5 years in patients with newly diagnosed glioblastoma treated with ICT-107 vaccine: A follow-up study. (2013). Paper presented at the fourth quadrennial meeting of the World Federation of Neurooncology, Abstract #IT-015.
(161) Press Release from ImmunoCellular Therapeutics, Sept. 11, 2013.
(162) Okada, H., Kalinski, P., Ueda, R., et al. Induction of CD8+ T-cell responses against novel glioma-associated antigen Peptides and clinical activity by vaccination with alpha-Type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma, J. Clin. Oncol., 2011, 29 (3), 330-36.
(163) Bloch, Orin et al. “Heat-shock protein peptide complex–96 vaccination for recurrent glioblastoma: a phase II, single-arm trial.” Neuro-oncology 16.2 (2014): 274-279.
(164) Agenus Brain Cancer Vaccine Shows Extended Survival in Phase 2 Final Data Analysis. July 1, 2014 press release.
(309) ImmunoCellular Therapeutics Presents Updated ICT-107 Phase II Data in Patients with Newly Diagnosed Glioblastoma at the 2014 ASCO Annual Meeting.
(320) Mitchell, Duane A et al. “Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients.” Nature 519.7543 (2015): 366-369.
Well, I hope you enjoyed reading, I was as faithful as possible. The next chapter will come very soon, however, after the publication of the latest research news for the first two months of 2021! See you soon!