Periodic Reporting for period 1 - PB_LC (Clinical readiness of a live biotherapeutic for treatment of Non-Small Cell Lung Cancer (NSCLC))
Periodo di rendicontazione: 2023-01-01 al 2023-12-31
Lung cancer (LC) is a major disease burden, standing as the second most diagnosed cancer and the leading cause of cancer-related deaths worldwide. In 2020, LC accounted for 2.2 million new cases and 1.8 million deaths globally, making up 11.4% of all cancer diagnoses and a substantial 18% of cancer-related deaths. Non-small cell lung cancer (NSCLC) is the predominant type, comprising 80%-87% of all lung cancer diagnoses. Regrettably, over 70% of NSCLC patients receive diagnoses in advanced stages (20% at Stage III, and 40%-46% at Stage IV), which complicates effective treatment and recovery.
Currently, the most common treatments for NSCLC are surgery, radiation, and immunotherapy, often employed in various combinations depending on the cancer stage, tumor size, and location. Among these, immune checkpoint inhibitors (ICI) therapy has gained prominence. ICI is a type of immune therapy consisting of antibodies that selectively block the interaction between proteins expressed on the surface of cancer cells and their corresponding receptors on T cells. Initially introduced in second and third-line settings for stage IV NSCLC, ICI exhibited response rates of around 20%, notably surpassing the 9–13% response rates observed with platinum-based chemotherapy. Crucially, a subset of patients experienced extended survival, prompting the integration of ICIs into first-line settings.
However, the efficacy of these inhibitors hinges on the immunogenicity of target tumors and the activation and infiltration of T cells into the tumor microenvironment, processes that do not consistently occur satisfactorily. Consequently, primary resistance is observed in 27.1% and 32.2% of patients in first- and second-line settings, respectively. Furthermore, a significant proportion of initially responsive patients develop secondary or acquired resistance, with a reported 65% acquired resistance to the anti-PD1 antibody nivolumab in NSCLC after a 4-year follow-up.
Against this backdrop, the average survival of advanced NSCLC patients remains low (2-4 years on average) and there is a great need for novel approaches and strategies aimed at reducing resistance to these therapies and rendering them more effective. Several novel agents have been tested in the clinic in combination with ICIs with the aim of overcoming resistance, including for example, oncolytic viruses, targeted therapies, cancer vaccines, adoptive cell transfer, epigenetic modulators, angiogenesis inhibitors and metabolism modulators in order to increase T cell infiltration within the tumour microenvironment, also known as converting a “cold” tumour into a “hot “tumour.
The PB_LC project seeks to develop a live biotherapeutic product based on a lung-specific bacterium, Mycoplasma pneumoniae, which can colonize and thrive in the microenvironment of lung tumors. Pulmobiotics’ founders have characterized this bacterium using “-omics” approaches to understand its biology and engineer therapeutic strains. This bacterium lacks cell wall, which allows it to secrete complex human proteins (such as cytokines) that cannot delivered by other bacteria like E. coli or Lactobacillus.
The product that we are developing (PB_LC) is intended for administration via inhalation, so it can secrete pro-inflammatory proteins in, and around, the tumor, stimulating the immune system, e.g. by promoting immune cell access, ultimately making a "cold" tumor "hot". The overarching goal of PB_LC is to enhance the effectiveness of ICIs and improve treatment outcomes in NSCLC patients.
Currently, the most common treatments for NSCLC are surgery, radiation, and immunotherapy, often employed in various combinations depending on the cancer stage, tumor size, and location. Among these, immune checkpoint inhibitors (ICI) therapy has gained prominence. ICI is a type of immune therapy consisting of antibodies that selectively block the interaction between proteins expressed on the surface of cancer cells and their corresponding receptors on T cells. Initially introduced in second and third-line settings for stage IV NSCLC, ICI exhibited response rates of around 20%, notably surpassing the 9–13% response rates observed with platinum-based chemotherapy. Crucially, a subset of patients experienced extended survival, prompting the integration of ICIs into first-line settings.
However, the efficacy of these inhibitors hinges on the immunogenicity of target tumors and the activation and infiltration of T cells into the tumor microenvironment, processes that do not consistently occur satisfactorily. Consequently, primary resistance is observed in 27.1% and 32.2% of patients in first- and second-line settings, respectively. Furthermore, a significant proportion of initially responsive patients develop secondary or acquired resistance, with a reported 65% acquired resistance to the anti-PD1 antibody nivolumab in NSCLC after a 4-year follow-up.
Against this backdrop, the average survival of advanced NSCLC patients remains low (2-4 years on average) and there is a great need for novel approaches and strategies aimed at reducing resistance to these therapies and rendering them more effective. Several novel agents have been tested in the clinic in combination with ICIs with the aim of overcoming resistance, including for example, oncolytic viruses, targeted therapies, cancer vaccines, adoptive cell transfer, epigenetic modulators, angiogenesis inhibitors and metabolism modulators in order to increase T cell infiltration within the tumour microenvironment, also known as converting a “cold” tumour into a “hot “tumour.
The PB_LC project seeks to develop a live biotherapeutic product based on a lung-specific bacterium, Mycoplasma pneumoniae, which can colonize and thrive in the microenvironment of lung tumors. Pulmobiotics’ founders have characterized this bacterium using “-omics” approaches to understand its biology and engineer therapeutic strains. This bacterium lacks cell wall, which allows it to secrete complex human proteins (such as cytokines) that cannot delivered by other bacteria like E. coli or Lactobacillus.
The product that we are developing (PB_LC) is intended for administration via inhalation, so it can secrete pro-inflammatory proteins in, and around, the tumor, stimulating the immune system, e.g. by promoting immune cell access, ultimately making a "cold" tumor "hot". The overarching goal of PB_LC is to enhance the effectiveness of ICIs and improve treatment outcomes in NSCLC patients.
When the PB_LC project started, mouse lung tumor models resistant to ICI had not been reported in the literature. We investigated the use of different mouse syngeneic cell lines and established a lung tumor model to study the impact of treatment on tumor lesion severity and another to study the impact of treatment on survival rate of the strains that will be engineered in the project.
We engineered 22 different bacterial strains based on an attenuated M. pneumoniae strain that secrete different combinations of pro-inflammatory payloads and tested their impact on the markers of immune response in vivo. We also assessed their growth rate and maintenance time in mouse lungs. Based on these data, 5 strains were selected for testing in the previously established mouse models.
We identified one strain that led to a significant reduction in tumor severity and stimulated immune cell infiltration. However, this strain did not improve animal survival in a statistically significant manner. We are now engineering strains that express additional payloads, with the aim of enhancing efficacy and improve response to anti-PD-L1 treatment of the already engineered strain, with the aim of nominating a clinical development candidate strain.
We engineered 22 different bacterial strains based on an attenuated M. pneumoniae strain that secrete different combinations of pro-inflammatory payloads and tested their impact on the markers of immune response in vivo. We also assessed their growth rate and maintenance time in mouse lungs. Based on these data, 5 strains were selected for testing in the previously established mouse models.
We identified one strain that led to a significant reduction in tumor severity and stimulated immune cell infiltration. However, this strain did not improve animal survival in a statistically significant manner. We are now engineering strains that express additional payloads, with the aim of enhancing efficacy and improve response to anti-PD-L1 treatment of the already engineered strain, with the aim of nominating a clinical development candidate strain.
To ensure success of the PB_LC project, given that the immune oncology field is currently very competitive, we are working to improve the efficacy of our bacterial strains and their ability to improve response to anti-PD-L1 treatment. Having a product with solid efficacy will be key to succeeding in clinical development and attracts potential commercial partners.
Another key aspect for the success of the project is to ensure that regulatory agencies approve the conduction of clinical trials with PB_LC. We have conducted a preliminary analysis of the regulatory pathway and feasibility of developing PB_LC, which confirmed that there are regulatory precedents for the development of this kind of therapy. We will start interacting with regulatory agencies in the EU once we have nominated a clinical development candidate and preliminary manufacturing and formulation data.
Finally, taking PB_LC to the market will require additional funding for clinical development. We have already established contacts with several European venture capital funds, which we will keep updated on our technical and business progress.
Another key aspect for the success of the project is to ensure that regulatory agencies approve the conduction of clinical trials with PB_LC. We have conducted a preliminary analysis of the regulatory pathway and feasibility of developing PB_LC, which confirmed that there are regulatory precedents for the development of this kind of therapy. We will start interacting with regulatory agencies in the EU once we have nominated a clinical development candidate and preliminary manufacturing and formulation data.
Finally, taking PB_LC to the market will require additional funding for clinical development. We have already established contacts with several European venture capital funds, which we will keep updated on our technical and business progress.