Periodic Reporting for period 1 - BraINstorm (Engineered nanocarriers for simultaneous anticancer immune response and “switching” of tumor-associated macrophages for intranasal glioblastoma treatment)
Período documentado: 2020-09-01 hasta 2022-08-31
Glioblastoma (GBM) is the most common, aggressive, and neurological destructive primary brain tumour in adults, among the most lethal human malignancies. An estimated 8-10,000 cases of GBM are diagnosed (in both sexes) every year. The current treatment includes safe maximal surgical resection of the accessible tumour followed by radiotherapy and chemotherapy combined with corticosteroids after three to four weeks. However, this approach is highly invasive, and not always applicable (40% of patients have unresectable GBM). Despite the invasive treatment, the prognosis for GBM is very poor and the patient's median survival is 14.6 months. Reasons behind the inefficacy of therapy against GBM reside in its anatomical location (the blood-brain barrier (BBB) precludes the passage of the majority of chemotherapy agents to the brain) and its aggressive tumour immune microenvironment (TIME) that plays a significant role in GBM progression and diffusion by stimulating angiogenesis and cell migration. In this context, immunotherapy has emerged as a potentially efficient means to treat cancers by turning the immune system against tumour cells. Notable progress in the field of immunotherapy has been made, particularly with the use of tumor vaccines; especially peptide vaccines and cell-based vaccines such as dendritic cell vaccines and tumor cell vaccines. Despite the impressive progression of immunotherapeutics and vaccination strategies, GBM remains a "cold," resistant, and deadly cancer. One solution is to break with traditional drug development paradigms and engineer the delivery of immunotherapeutics to target tissues (GBM or lymph nodes) or cell types to control the timing/location of immunomodulation. To achieve this goal, nanomedicine-based approaches offer a means to increase immunotherapeutic efficacy.
Due to the high incidence of GBM in European citizens and the observation of 70% of cases in patients between 45 and 70 years, the need for new therapeutic approaches will have significant social, clinical, and economic relevance and impact. Furthermore, the socioeconomic burden of GBM will be reduced by diminishing side effects and treatment costs. We also speculate that our strategy can be translated into other cancer types lacking immunotherapy approaches (e.g. brain metastasis and pediatric tumours). We developed the proposed research project with the knowledge that innovation alone is not sufficient for the development of an original scientific project; we must also answer patient needs and impact lifestyles.
Due to the high incidence of GBM in European citizens and the observation of 70% of cases in patients between 45 and 70 years, the need for new therapeutic approaches will have significant social, clinical, and economic relevance and impact. Furthermore, the socioeconomic burden of GBM will be reduced by diminishing side effects and treatment costs. We also speculate that our strategy can be translated into other cancer types lacking immunotherapy approaches (e.g. brain metastasis and pediatric tumours). We developed the proposed research project with the knowledge that innovation alone is not sufficient for the development of an original scientific project; we must also answer patient needs and impact lifestyles.
The ultimate goal of BraINstorm is to develop new drug delivery systems to enhance and potentiate immunotherapies against GBM using hyaluronic acid (HA) as a delivery strategy. An HA-based combination immunoconjugate would tackle GBM through a synergistic approach: i) the delivery of an immunomodulatory oligonucleotide (CpG) that promotes M2-like macrophages polarization into M1-like associated (anti-cancer, TAMs) with doxorubicin (DOX) an anticancer drug able to induce immunogenic cell death (ICD) inducing the process of the adaptative immune response; ii) the stimulation of the immune system via the delivery of Glioblastoma-associated antigens.
In the first part of the project, we developed a local combination therapy. We studied the impact of in situ combinations of DOX and CpG on GBM by understanding their effect on the local immune system and developing a rationally designed nanocarrier aimed at enhancing the performances of single and combined therapeutic agents. We demonstrate that a single intratumoral delivery of HA-DOX + HA-CpG can induce long-term survival in > 66% of GBM-bearing animals. In addition, we report that the local administration of HA conjugates stimulates immune responses, provoking a shift in the GBM immune landscape and immune-mediated anti-GBM activity. These findings show that HA-DOX and HA-CpG in combination have the potential for clinical translation as a treatment option for patients bearing unresectable GBM.
In the second part of the project, HA has been conjugated into two distinct tumor-associated antigens; TRP2 and GP100. These antigens are overexpressed by the tumor cells and not present (or less expressed) in normal cells; therefore, they can be used as specific antigens for eliciting immune responses against cancer. We hypothesized that the concurrent delivery of a combination of antigens conjugated to HA could overcome the limitations associated with current immunotherapies. The novel HA-nanovaccine has been tested in a proof-of-concept model of melanoma. This model is responsive to vaccines and allowed us to 1) explore the efficacy of HA-nanovaccines in a prophylactic and therapeutic setting to validate the efficacy of the novel vaccine; 2) explore the infiltration of T-cells in a model that has a superior level of T cells concerning GBM. Our results show that HA-nanovaccine co-administered with CpG as an adjuvant has high tropism to LNs and elicits a systemic immune response superior to free peptides. Importantly, we demonstrate that concurrent delivery of combined antigens exerts effective responses to delay the growth of the immune-refractory advanced melanoma model in prophylactic and therapeutic settings. Importantly, this study highlights the role of HA-nanovaccines in enhancing T-cell infiltration at the tumor site and extending survival.
Next, the efficacy of HA-nanovaccine has been explored in a GBM model. Despite we observed a superior infiltration of immune cells at day 21, no benefits were found in terms of survival. We hypothesized that a complementary in situ treatment to re-educate the TIME would help the novel HA-nanovaccine in enhancing the immune response.
Altogether, these results highlight the need for new therapeutic platforms to simultaneously boost the immune system and reshape the tumour immune microenvironment to enhance T cells' infiltration. We believe that this approach will improve the patient immune system against GBM.
In the first part of the project, we developed a local combination therapy. We studied the impact of in situ combinations of DOX and CpG on GBM by understanding their effect on the local immune system and developing a rationally designed nanocarrier aimed at enhancing the performances of single and combined therapeutic agents. We demonstrate that a single intratumoral delivery of HA-DOX + HA-CpG can induce long-term survival in > 66% of GBM-bearing animals. In addition, we report that the local administration of HA conjugates stimulates immune responses, provoking a shift in the GBM immune landscape and immune-mediated anti-GBM activity. These findings show that HA-DOX and HA-CpG in combination have the potential for clinical translation as a treatment option for patients bearing unresectable GBM.
In the second part of the project, HA has been conjugated into two distinct tumor-associated antigens; TRP2 and GP100. These antigens are overexpressed by the tumor cells and not present (or less expressed) in normal cells; therefore, they can be used as specific antigens for eliciting immune responses against cancer. We hypothesized that the concurrent delivery of a combination of antigens conjugated to HA could overcome the limitations associated with current immunotherapies. The novel HA-nanovaccine has been tested in a proof-of-concept model of melanoma. This model is responsive to vaccines and allowed us to 1) explore the efficacy of HA-nanovaccines in a prophylactic and therapeutic setting to validate the efficacy of the novel vaccine; 2) explore the infiltration of T-cells in a model that has a superior level of T cells concerning GBM. Our results show that HA-nanovaccine co-administered with CpG as an adjuvant has high tropism to LNs and elicits a systemic immune response superior to free peptides. Importantly, we demonstrate that concurrent delivery of combined antigens exerts effective responses to delay the growth of the immune-refractory advanced melanoma model in prophylactic and therapeutic settings. Importantly, this study highlights the role of HA-nanovaccines in enhancing T-cell infiltration at the tumor site and extending survival.
Next, the efficacy of HA-nanovaccine has been explored in a GBM model. Despite we observed a superior infiltration of immune cells at day 21, no benefits were found in terms of survival. We hypothesized that a complementary in situ treatment to re-educate the TIME would help the novel HA-nanovaccine in enhancing the immune response.
Altogether, these results highlight the need for new therapeutic platforms to simultaneously boost the immune system and reshape the tumour immune microenvironment to enhance T cells' infiltration. We believe that this approach will improve the patient immune system against GBM.
With the MSCA BraINstorm, we wanted to overcome the limitation associated with the immunotherapy of Glioblastoma using Hyaluronic acid as a drug delivery platform to harness the immune system against GBM. Our results highlight that Hyaluronic acid as a nanocarrier for anticancer vaccines elicits an immune response towards cancer cells. In the specific case of GBM, in order to have extended survival, a complementary approach is required via a local reshaping of the tumour microenvironment. The novelty of our strategy resides in targeting multiple arms of GBM immunity at the same time provoking a shift in the GBM immune landscape aiming to extend survival. Moreover, our findings demonstrate this new approach has the potential for clinical translation as a treatment option for patients bearing unresectable GBM. Our strategy has the advantages (i) of using biomaterials that facilitate translation into the clinic; (ii) of having effective scale-up options and being easy to handle and apply by neurosurgeons and (iii) the potential to form hydrogels adaptable to fill a tumour-resected niche, which is a step closer to the standard of care. In the future, this local treatment might be implemented and applied to tackle various forms of “cold” cancer. The outcome of the research of BraiINstorm will open new perspectives in the preclinical and clinical management of GBM.