Cancer immunotherapy by immune checkpoint blockade has proven its great potential by saving the lives of a proportion of late stage patients with immunogenic tumor types. However, even in these sensitive tumor types, the majority of patients do not sufficiently respond to the therapy. Furthermore, other tumor types, including glioblastoma, remain largely refractory. The glioblastoma immune microenvironment is recognized as highly immunosuppressive, posing a major hurdle for inducing immune-mediated destruction of cancer cells. Scattered information is available about the presence and activity of immunosuppressive or immunostimulatory cell types in glioblastoma tumors, including tumor-associated macrophages, tumor-infiltrating dendritic cells and regulatory T cells. These cell types are heterogeneous at the level of ontogeny, spatial distribution and functionality within the tumor immune compartment, providing insight in the complex cellular and molecular interplay that determines the immune refractory state in glioblastoma. This knowledge may also yield next generation molecular targets for therapeutic intervention.

Understanding the glioblastoma immune microenvironment as basis for the development of new immunotherapeutic strategies.

Glioblastoma is a highly lethal brain cancer with a median survival rate of less than 15 months when treated with the current standard of care, which consists of surgery, radiotherapy and chemotherapy. With the recent success of immunotherapy in other aggressive cancers such as advanced melanoma and advanced non-small cell lung cancer, glioblastoma has been brought to the forefront of immunotherapy research. Resistance to therapy has been a major challenge across a multitude of experimental candidates and no immunotherapies have been approved for glioblastoma to-date. Intra- and inter-tumoral heterogeneity, an inherently immunosuppressive environment and tumor plasticity remain barriers to be overcome. Moreover, the unique tissue-specific interactions between the central nervous system and the peripheral immune system present an additional challenge for immune-based therapies. Nevertheless, there is sufficient evidence that these challenges may be overcome, and immunotherapy continues to be actively pursued in glioblastoma. Herein, we review the primary ongoing immunotherapy candidates for glioblastoma with a focus on immune checkpoint inhibitors, myeloid-targeted therapies, vaccines and chimeric antigen receptor (CAR) immunotherapies. We further provide insight on mechanisms of resistance and how our understanding of these mechanisms may pave the way for more effective immunotherapeutics against glioblastoma.

/pdf/immunotherapy-for-glioblastoma-current-progress-and-20v2djag9u.pdf

Immunotherapy for Glioblastoma: Current Progress and Challenge

The tumor microenvironment (TME) influences tumor growth, metastatic spread and response to treatment. Often immunosuppression, mediated by the TME, impairs a beneficial response. The complexity of the tumor composition challenges our abilities to design new and more effective therapies. Going forward we will need to ‘manage’ the content and or functionality of the TME to improve treatment outcomes. Currently, several different kinds of treatments are available to patients with cancer: there are the traditional approaches of chemotherapy, radiation and surgery; there are targeted agents that inhibit kinases associated with oncogenic pathways; there are monoclonal antibodies that target surface antigens often delivering toxic payloads or cells and finally there are antibodies and biologics that seek to overcome the immunosuppression caused by elements within the TME. How each of these therapies interact with the TME is currently under intense and widespread investigation. In this review we describe how the TME and its immunosuppressive components can influence both tumor progression and response to treatment focusing on three particular tumor types, classic Hodgkin Lymphoma (cHL), Pancreatic Ductal Adenocarcinoma (PDAC) and Glioblastoma Multiforme (GBM). And, finally, we offer five approaches to manipulate or manage the TME to improve outcomes for cancer patients.

/pdf/managing-the-tme-to-improve-the-efficacy-of-cancer-therapy-3bf4qe4v.pdf

Managing the TME to improve the efficacy of cancer therapy

Glioblastoma (GBM) treatment has remained almost unchanged for more than 20 years. The current standard of care involves surgical resection (if possible) followed by concomitant radiotherapy and chemotherapy. In recent years, immunotherapy strategies have revolutionized the treatment of many cancers, increasing the hope for GBM therapy. However, mostly due to the high, multifactorial immunosuppression occurring in the microenvironment, the poor knowledge of the neuroimmune system and the presence of the blood-brain barrier, the efficacy of immunotherapy in GBM is still low. Recently, new strategies for GBM treatments have employed immunotherapy combinations and have provided encouraging results in both preclinical and clinical studies. The lessons learned from clinical trials highlight the importance of tackling different arms of immunity. In this review, we aim to summarize the preclinical evidence regarding combination immunotherapy in terms of immune and survival benefits for GBM management. The outcomes of recent studies assessing the combination of different classes of immunotherapeutic agents (e.g., immune checkpoint blockade and vaccines) will be discussed. Finally, future strategies to ameliorate the efficacy of immunotherapy and facilitate clinical translation will be provided to address the unmet medical needs of GBM. 

/pdf/immunotherapy-for-glioblastoma-the-promise-of-combination-20d1k61m.pdf

Immunotherapy for glioblastoma: the promise of combination strategies

Bacteria can bypass the blood-brain barrier (BBB), suggesting the possibility of employment of bacteria for combating central nervous system diseases. Herein, we develop a bacteria-based drug delivery system for glioblastoma (GBM) photothermal immunotherapy. The system, which we name as 'Trojan bacteria', consists of bacteria loaded with glucose polymer and photosensitive ICG silicon-nanoparticles. In an orthotopic GBM mouse model, we demonstrate that the intravenously injected bacteria bypass the BBB, targeting and penetrating GBM tissues. Upon 808 nm-laser irradiation, the photothermal effects produced by ICG allow the destruction of bacterial cells and the adjacent tumour cells. Furthermore, the bacterial debris as well as the tumour-associated antigens promote antitumor immune responses that prolong the survival of GBM-bearing mice. Moreover, we demonstrate the residual bacteria are effectively eliminated from the body, supporting the potential therapeutic use of this system. 

https://www.nature.com/articles/s41467-022-32837-5.pdf

Bacteria loaded with glucose polymer and photosensitive ICG silicon-nanoparticles for glioblastoma photothermal immunotherapy

Background: Although programmed death-1 (PD-1) blockade is effective in treating several types of cancer, the efficacy of this agent in glioblastoma (GBM) is largely unknown. Methods: We evaluated therapeutic effects of anti-PD-1, temozolomide (TMZ), and their combination in an orthotopic murine GBM model. The phenotype, number, and composition of lymphocytes were evaluated using flow cytometry. Transcriptional profiles of tumor tissues were analyzed using microarrays. Generation of antitumor immunological memory was investigated upon rechallenge. Results: Combined treatment with anti-PD-1 and TMZ yielded synergistic antitumor efficacy in the presence of donor-originated PD-1+CD8+ T cells in vitro, necessitating in vivo validation. Whereas TMZ did not rescue GBM-implanted mice, anti-PD-1 completely eradicated GBM in 44.4% of mice, and combination of anti-PD-1 and TMZ in all mice. Anti-PD-1 significantly increased the number of tumor-infiltrating lymhpocytes (TILs), and reduced frequencies of exhausted T cells and regulatory T cells. However, combining TMZ with anti-PD-1 significantly decreased the number of TILs, which was also observed with TMZ treatment alone. A transcriptome analysis of tumor tissues revealed that anti-PD-1 monotherapy perturbed immune-related genes, distinctly with combined therapy. Upon rechallenge, tumor growth was not observed in mice cured by anti-PD-1 monotherapy, whereas tumors regrew in the combination group. Furthermore, an analysis of peripheral blood revealed that antitumor memory T cells were generated in mice cured by anti-PD-1 monotherapy, not in the combination group. Conclusion: PD-1 blockade induces long-term therapeutic response, and combination with TMZ further enhances antitumor efficacy. However, immunological memory is provoked by anti-PD-1 monotherapy, not by combined therapy.

https://www.tandfonline.com/doi/pdf/10.1080/2162402X.2018.1525243

Effect of combined anti-PD-1 and temozolomide therapy in glioblastoma.

Glioblastoma (GBM) is the most common and aggressive human primary brain malignancy. The key properties of GBM, stemness and invasiveness, are known to be associated with a highly unfavorable prognosis. Notably, the process of epithelial-mesenchymal transition (EMT) is closely related to the progression of GBM. On the basis of reports that 2′-hydroxycinnamaldehyde (HCA) and its derivative, 2′-benzoyloxycinnamaldehyde (BCA), suppresses EMT in several human cancer cells, we sought to evaluate the therapeutic efficacy of HCA and BCA, alone and in combination with temozolomide (TMZ), on GBM tumorspheres (TSs). Two human GBM TSs were treated with HCA, BCA, or TMZ. Therapeutic effects were evaluated by measuring ATP levels, neurosphere formation, 3D-invasion in collagen matrix, and viability. Protein expression profiles after drug treatment were evaluated by western blotting. In vivo anticancer efficacy of drugs was examined in a mouse orthotopic xenograft model. Combined treatment of GBM TSs with HCA or BCA and TMZ significantly reduced cell viability, stemness, and invasiveness. Expression levels of stemness-, invasiveness-, and mesenchymal transition-associated markers, Zeb1, N-cadherin, and β-catenin, were also substantially decreased by the combined treatment. The combined treatment also reduced tumor growth in a mouse orthotopic xenograft model. Our findings suggest that HCA and BCA, combined with TMZ, are potential therapeutic agents in the treatment of GBM.

Combined treatment with 2'-hydroxycinnamaldehyde and temozolomide suppresses glioblastoma tumorspheres by decreasing stemness and invasiveness.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor with a poor prognosis despite multimodal interventions. For brain tumors, immunotherapy has not yet fully proved their potential. The central nervous system has historically been regarded as an immune privileged organ, throwing doubt on application of immunotherapy to GBM. However, growing evidences suggest that immune cells can traverse the blood-brain barrier and affect immune responses in the brain. Although immunotherapy by programmed cell death protein 1 (PD-1) blockade has dramatically improved the survival rate of some types of cancer patients, its application to GBM still needs further investigation. To improve efficacy of immunotherapy, there have been many attempts for finding effective combination partner in several types of tumors. We hypothesized that TMZ could work synergistically with PD-1 blockade to generate a robust antitumor response against GBM. Here, we evaluated therapeutic responses of PD-1 blockade and its combination with temozolomide (TMZ) in mouse GBM model. PD-1 blockade remarkably showed long-term antitumor effects, and combined use of TMZ further improved survival rate. However, distinct working mechanisms operated in these two therapeutic strategies. Anti-PD-1 monotherapy significantly augmented the number of tumor-infiltrating lymphocytes and protected them from exhaustion. In comparison, TMZ combination abrogated these effects, suggesting that superior therapeutic efficacy did not originated from increased immune responses. Microarray experiments revealed that anti-PD-1 and combination groups differentially converted transcriptional programs, particularly emphasized by mutually exclusive functional annotation by ImmuneSigDB gene sets. Moreover, tumor rechallenge study showed that immunologic memory was generated only in the anti-PD-1 monotherapy group. Although TMZ did not facilitate anti-PD-1-mediated immune response or memory function, these data suggest that combined treatment of anti-PD-1 and TMZ exert robust antitumor efficacy with therapeutic benefits in GBM. In addition, our data suggest possibility of immunotherapy to be added in standard treatment modalities of GBM.

/pdf/immu-16-effect-of-anti-pd-1-therapy-combination-on-2jo72loqcw.pdf

Immu-16. effect of anti-pd-1 therapy combination on temozolomide in mouse glioblastoma.

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Effect of combined anti-PD-1 and temozolomide therapy in glioblastoma.

Combined treatment with 2'-hydroxycinnamaldehyde and temozolomide suppresses glioblastoma tumorspheres by decreasing stemness and invasiveness.

Immu-16. effect of anti-pd-1 therapy combination on temozolomide in mouse glioblastoma.