March 2015, Vol. 2, No. 2

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Vaccines for Glioblastoma

Uncategorized

Cancer vaccines, which depend on activation of the patient’s immune system to recognize and destroy the tumor, have the potential for eliciting a widespread and durable response

More than a century ago, researchers began using vaccination to fight cancer. They injected patients with cells and extracts from their own tumors, or tumors of the same type from different individuals, in an attempt to stimulate a tumor-specific, therapeutic immune response to tumors.1 Today, a number of vaccines are under investigation for the treatment of patients with glioblastoma (Table).



Cancer vaccines harness the potent antigen-presenting capabilities of dendritic cells, which have the ability to stimulate primary T-cell antitumor immune responses. Dendritic cells, part of the innate immune system, incorporate antigens and subsequently present them to the cells of the adaptive immune system to initiate an immune response. Dendritic cells can be removed from the body and modified ex vivo to enhance specific antigen presentation or can be activated in vivo to the same end.2

ICT-107

ICT-107 is an autologous vaccine consisting of the patient’s dendritic cells pulsed with 6 synthetic tumor- associated antigens (AIM-2, MAGE-1, TRP-2, gp100, HER2, IL-13R?2) that are commonly expressed by glioblastoma stem cells or glioblastoma tumors.2 Results from a small, single-institution, phase 1 study of ICT-107 in 16 newly diagnosed patients with glioblastoma showed that median progression-free survival (PFS) was 16.9 months, and the 5-year rate of PFS was 37.5%; median overall survival (OS) was 38.4 months, and the 5-year rate of OS was 50%.3

Based on the results from this phase 1 study, a multicenter, randomized, double-blind, placebo-controlled, phase 2 study (NCT01280552) of the safety and efficacy of ICT-107 was conducted in 124 patients newly diagnosed with glioblastoma following resection and chemoradiation. The study included patients with human leukocyte antigen-A1 (HLA-A1)-positive or HLA-A2–positive glioblastoma. All patients received standard-of-care temozolomide, and 81 patients were randomized to receive the ICT-107 vaccine and 43 patients to receive placebo (their own dendritic cells not exposed to antigen). The primary end point of the study was OS.4

Updated results from this study, which were presented in November 2014 at the 19th Annual Scientific Meeting and Education Day of the Society for Neuro-Oncology, failed to demonstrate a statistically significant improvement in OS. In the intent-to-treat (ITT) population, median OS was 18.3 months for the ICT-107 group and 16.7 for the control group, representing a numeric, but not statistically significant, advantage for the treatment group (age-stratified hazard ratio [HR] 0.854 [0.547-1.334]; P = .487; (Figure 1).5 However, a statistically significant improvement was seen in PFS among those patients who received the vaccine. Median PFS in the ITT population was 11.4 months for the ICT-107 group and 10.1 months for the control group, representing a statistically significant benefit in the ICT-107 group (age-stratified HR 0.64 [0.42-0.97]; P = .033).



The methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter (which is thought to contribute to cellular DNA repair) is an important molecular factor in glioblastoma tumors. Methylation of the gene promoter in the tumor tissue silences the expression of MGMT and has been found to be a prognostic and potentially predictive marker for benefit from temozolomide treatment in patients with newly diagnosed glioblastoma. Because of this, subgroup analyses, including HLA-A2 patients within each of the 2 major MGMT subgroups (unmethylated and methylated), were conducted in the phase 2 ICT-107 study. When survival was assessed in these prespecified patient subgroups, results favored treatment with ICT-107 over control in HLA-A2 patients within both the unmethylated and methylated HLA-A2 MGMT subgroups.5 Median PFS for the HLA-A2 unmethylated MGMT per-protocol (PP) population was 10.5 months for the ICT-107 group and 6.0 months for the control group, representing a 4.5-month median PFS benefit for the ICT-107 group (age-stratified HR 0.72 [0.35-1.47]; P = .364). Median PFS for the HLA-A2 methylated MGMT PP population was 24.1 months for the ICT-107 group and 8.5 months for the control group, representing a statistically significant 15.6-month PFS benefit for the ICT-107 group (age-stratified HR 0.257 [0.095-0.697]; P = .004). No differences in adverse events were seen between the 2 groups.5

DCVax-L

DCVax-L (also known as DCVax-Brain or DCVax) is a dendritic cell vaccine derived from autologous dendritic cells pulsed with a patient-specific tumor lysate. DCVax-L has been studied in 2 small, completed, single-arm, phase 1 studies.6 In the first single-arm, phase 1 study (N = 12), 7 patients with newly diagnosed glioblastoma and 5 with recurrent glioblastoma received DCVax-L in addition to standard-of-care treatment (which included reoperation, temozolomide, and/or other medications).7 The median time to progression for these 12 patients was 15.5 months (vs 8.2 months for a matched control group), and the median OS time was 23.4 months (vs 18.3 months for a matched control group). In the second single-arm phase 1 study (NCT00068510; N = 23), 15 patients with newly diagnosed glioblastoma and 8 with recurrent glioblastoma received DCVax-L in conjunction with toll-like receptor agonists (ie, either 5% imiquimod cream or intramuscular injections of poly interstitial Cajal-like cell [ICLC] adjuvant) until tumor progression.8 The median time to progression was reported as 15.9 months and median OS as 31.4 months. Among the 15 newly diagnosed patients, the median OS was 35.9 months.

Based on these results, an international, multicenter, double-blind, randomized, placebo-controlled phase 3 study (NCT00045968) is being conducted in 348 patients with newly diagnosed glioblastoma.6,9 Patients will receive the standard-of-care treatment (including radiation and temozolomide), and one group will receive DCVax-L whereas the other group will receive a placebo. The primary end point of the study is PFS.

Also based on the results from the above-mentioned phase 1 study (NCT00068510) in which patients received DCVax-L in conjunction with toll-like receptor agonists, a placebo-controlled phase 2 study (NCT01204684) is under way at Jonsson Comprehensive Cancer Center in Los Angeles by the same investigators to evaluate the vaccine in combination with either 0.2% imiquimod cream, a single intramuscular injection of poly ICLC, or placebo.10

An open-label, phase 1 study (NCT01792505) is also under way at Cedars-Sinai Medical Center in Los Angeles in which patients undergo surgical resection followed by vaccination with dendritic cells pulsed with tumor lysate in combination with imiquimod cream application.11

Heat Shock Protein Peptide-Based Vaccines

The expression of heat shock proteins (HSPs), a group of ubiquitous soluble intracellular proteins, is increased when cells are exposed to elevated temperatures or other stresses.12 HSP-peptide complexes (HSPPCs) found in cancer cells carry tumor-specific antigenic proteins and can facilitate adaptive and innate immune responses.12,13 An HSPPC vaccine based on tumor-derived glycoprotein 96 (HSPPC-96) has been studied as a single agent in a phase 2 study in recurrent glioblastoma.13 Results from this multicenter, open-label study (N = 41) showed that, in the ITT population, the median PFS was 19.1 weeks (95% CI, 14.1-24.1), with a 6-month PFS of 29.3% (95% CI, 16.6-45.7); the median OS was 42.6 weeks (95% CI, 34.7-50.5), with a 6-month OS of 90.2% (95% CI, 75.9-96.8) and a 12-month OS of 29.3% (95% CI, 16.6-45.7; (Figure 2).14



A phase 2 study of HSPPC-96 has also been completed in patients with newly diagnosed glioblastoma in combination with radiation therapy and temozolomide chemotherapy (NCT00905060). Preliminary results from this study showed that patients treated with HSPPC-96 plus the standard of care (radiation and temozolomide) had a median OS of approximately 24 months, and 33% of patients remained alive at 2 years and continue to be followed for survival.15 In addition to the long-term survival data, patients treated with HSPPC-96 had a median PFS of nearly 18 months, 2 to 3 times longer than patients treated with radiation and temozolomide alone.15,16 Furthermore, 22% of patients were alive and without progression at 24 months and continue to be followed for survival (Figure 3).15



A large-scale phase 2, randomized 3-group study (NCT01814813) of HSPPC-96 in combination with bevacizumab (given concomitantly or at the point of progression) versus bevacizumab alone in recurrent glioblastoma is being conducted by the National Cancer Institute.17

References

  1. Myc LA, Gamian A, Myc A. Cancer vaccines. Any future? Arch Immunol Ther Exp (Warsz). 2011;59:249-259.
  2. Xu LW, Chow KK, Lim M, et al. Current vaccine trials in glioblastoma: a review. J Immunol Res. 2014;2014:796856.
  3. Phuphanich S, Wheeler CJ, Rudnick JD, et al. Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol Immunother. 2013;62:125-135.
  4. Wen PY, Reardon DA, Phuphanich S, et al. A randomized, double-blind, placebo-controlled phase 2 trial of dendritic cell (DC) vaccination with ICT-107 in newly diagnosed glioblastoma (GBM) patients. J Clin Oncol. 2014;32(suppl). Abstract 2005.
  5. ImmunoCellular Therapeutics. ICT-107. www.imuc.com/pipeline/ict-107. Accessed February 4, 2015.
  6. Northwest Biotherapeutics. DCVax® – L phase III for GBM brain cancer. www.nwbio.com/clinical-trials/dcvax-l-phase-iii-for-gbm-brain-cancer/. Accessed February 4, 2015.
  7. Liau LM, Prins RM, Kiertscher SM, et al. Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin Cancer Res. 2005;11:5515-5525.
  8. Prins RM, 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. Clin Cancer Res. 2011;17:1603-1615.
  9. ClinicalTrials.gov. Study of a drug [DCVax®-L] to treat newly diagnosed GBM brain cancer. www.clinicaltrials.gov/ct2/show/study/NCT00045968. Accessed February 4, 2015.
  10. ClinicalTrials.gov. Dendritic cell vaccine for patients with brain tumors. https://clinicaltrials.gov/ct2/show/NCT01204684. Accessed February 4, 2015.
  11. ClinicalTrials.gov. Dendritic cell vaccine with imiquimod for patients with malignant glioma. https://clinicaltrials.gov/show/NCT01792505. Accessed February 4, 2015.
  12. Amato RJ. Heat-shock protein-peptide complex-96 for the treatment of cancer. Expert Opin Biol Ther. 2007;7:1267-1273.
  13. Crane CA, Han SJ, Ahn B, et al. Individual patient-specific immunity against high-grade glioma after vaccination with autologous tumor derived peptides bound to the 96 KD chaperone protein. Clin Cancer Res. 2013;19:205-214.
  14. Bloch O, Crane CA, Fuks Y, et al. Heat-shock protein peptide complex-96 vaccination for recurrent glioblastoma: a phase II, single-arm trial. Neuro Oncol. 2014;16:274-279.
  15. Agenus. Agenus brain cancer vaccine shows extended survival in phase 2 final data analysis [press release]. www.agenusbio.com/docs/press-releases/2014/agenus-brain-cancer-vaccine-shows-extended-survival-in-phase-2-final-data-analysis.php. July 1, 2014. Accessed February 10, 2015.
  16. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987-996.
  17. ClinicalTrials.gov. Vaccine therapy with bevacizumab versus bevacizumab alone in treating patients with recurrent glioblastoma multiforme that can be removed by surgery. https://clinicaltrials.gov/ct2/show/NCT01814813?term=NCT01814813&ra nk=1. Accessed February 4, 2015.
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