Although no dose-limiting toxicity was observed and CAR T cell persistence was noted up to 12 months post-infusion, no significant survival benefit was noted for treated patients with a median overall survival of 11

Although no dose-limiting toxicity was observed and CAR T cell persistence was noted up to 12 months post-infusion, no significant survival benefit was noted for treated patients with a median overall survival of 11.1 months. 5. that revitalize the anti-tumor immune response, several immunotherapeutic modalities have been developed for treatment of GBM. In this review, we summarize recent clinical and preclinical efforts to evaluate vaccination strategies, immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T cells. Although these modalities have shown long-term Pyrazofurin tumor regression in subsets of treated patients, the underlying biology that may predict efficacy and inform therapy development is being actively investigated. Common to all therapeutic modalities are fundamental mechanisms of therapy evasion by tumor cells, including immense intratumoral heterogeneity, Mouse monoclonal to EGF suppression of the tumor immune microenvironment and low mutational burden. These insights have led efforts to design rational combinatorial therapies that can reignite the Pyrazofurin anti-tumor immune response, effectively and specifically target tumor cells and reliably decrease tumor burden for GBM patients. 100) reaching 40.5 months. Primary GBM Liau et al. [22]”type”:”clinical-trial”,”attrs”:”text”:”NCT00293423″,”term_id”:”NCT00293423″NCT00293423HSPPC-96 peptide vaccineSpecific immune response in 11 of the 12 patients, responders had median overall survival of 11.8 months. Recurrent GBM Crane et al. [23]232) were vaccinated and given concurrent TMZ, while all patients (331) were given the vaccine upon tumor recurrence. The overall study population had a median survival of 23.1 months, with a large group (100) having a particularly long median survival of 40.5 months unexplained by any prognostic factors, suggesting clinical efficacy related to vaccination [22]. A trial is now ongoing in patients who were previously ineligible due to post-chemoradiotherapy progression or insufficient vaccine production (“type”:”clinical-trial”,”attrs”:”text”:”NCT02146066″,”term_id”:”NCT02146066″NCT02146066). As an alternative approach to pulsing DCs with tumor lysate, DCs pulsed with a synthetic cocktail of tumor-associated antigens have shown promising preliminary results, with 5 of 16 vaccine-treated GBM patients surviving 6 years post-diagnosis [41,42]. Vaccines relying on heat shock proteins (HSP) are also being explored for GBM treatment. There have been several trials investigating HSP vaccines for glioma, which consist of HSPs and tumor-associated peptides. These vaccines primarily rely on tumor-derived HSP glycoprotein 96 (gp96), which binds tumor antigens forming the HSP protein complex-96 (HSPPC-96). This complex mediates presentation of antigens in antigen-presenting cells and can bind different peptides for a multi-targeted approach. An initial trial of a multi-peptide HSPPC-96 vaccine with TMZ (“type”:”clinical-trial”,”attrs”:”text”:”NCT00293423″,”term_id”:”NCT00293423″NCT00293423) confirmed strong peripheral and local immune responses specific to HSPPC-96-bound antigens in 11 of 12 treated patients [23]. These responders had a median survival of 11.8 months post-vaccination and surgery compared to 4 months for the single non-responding patient, and in the phase II portion of this trial, patients showed a median survival of 10.7 months, significantly exceeding controls [24]. Additionally, patients with pre-vaccination lymphopenia had decreased survival compared to those with higher lymphocyte counts, likely due to worsened immune function and thus decreased responses. Addressing this question and further validating effectiveness of this vaccine, another trial (“type”:”clinical-trial”,”attrs”:”text”:”NCT02122822″,”term_id”:”NCT02122822″NCT02122822) revealed those with strong tumor-specific immune responses indeed had longer median survival than those with Pyrazofurin weak responses (>40.5 months and 14.6 months, respectively), with the overall patient population reaching a median survival of 31.4 months and again exceeding controls [25]. Another phase II trial was recently completed with the HSPPC-96 vaccine and TMZ following SoC (“type”:”clinical-trial”,”attrs”:”text”:”NCT00905060″,”term_id”:”NCT00905060″NCT00905060), achieving a median survival of 23.8 months, further validating efficacy of this vaccine [26]. Interestingly, this trial found expression of the T cell-suppressing immune checkpoint PD-L1 in myeloid cells to be indicative of survival, with high expression leading to shorter survival as compared to patients with lower PD-L1 expression (18 months and 44.7 months, respectively). While a promising lead, no HSPPC-96 vaccines have been combined with anti-PD-L1 therapies to date. However, a trial is currently investigating the vaccine when combined with standard TMZ, radiotherapy and the antibody pembrolizumab targeting the PD-L1 receptor, which is ongoing (“type”:”clinical-trial”,”attrs”:”text”:”NCT03018288″,”term_id”:”NCT03018288″NCT03018288). 3. Antibodies Modulating the Tumor Immune Microenvironment A complex system of stimulatory and inhibitory regulators functions to maintain immune homeostasis. An important part of this system is immune checkpoints, which regulate activation to avoid autoimmunity. Upon activation or exhaustion, several immune cells upregulate these inhibitory checkpoints, thus limiting the immune response. Cancer cells express immune checkpoint proteins as well, allowing them to suppress the anti-cancer immune response. As a result, antibodies against these checkpoints, known as immune checkpoint inhibitors (ICI), have shown success in several cancers such as melanoma and non-small-cell lung cancer [43], and several are being tested for GBM (Table 2). Of these antibodies, the.