Our technology

PD-L1 and autoimmune disorders

 

Programmed death-ligand 1 (PD-L1) is a checkpoint molecule involved in the control of reactive T cells. Harnessing the power of the immune-regulatory protein PD-L1 can lead to overcome the onset of autoimmune reactions and to promote immune tolerance.
The expression of PD-L1 onto hematopoietic stem and progenitor cells of patients with autoimmune diseases, including type 1 diabetes, is either lacking or is significantly decreased. The restoration of PD-L1 expression by lentiviral vector-based gene therapy successfully reverse type 1 diabetes in the gold-standard disease animal model, the non-obese diabetic mouse model, achieving not only the control of glucose blood levels but also the normalization of pancreatic histology and function, preserving the endogenous production of insulin.
The use of the same technology in investigational mouse models of multiple sclerosis demonstrates clinical benefits by direct delivery of the engineered hematopoietic and progenitor stem cells into the central nervous system.

PD-L1 and autoimmune disorders

 

Programmed death-ligand 1 (PD-L1) is a checkpoint molecule involved in the control of reactive T cells. Harnessing the power of the immune-regulatory protein PD-L1 can lead to overcome the onset of autoimmune reactions and to promote immune tolerance.
The expression of PD-L1 onto hematopoietic stem and progenitor cells of patients with autoimmune diseases, including type 1 diabetes, is either lacking or is significantly decreased. The restoration of PD-L1 expression by lentiviral vector-based gene therapy successfully reverse type 1 diabetes in the gold-standard disease animal model, the non-obese diabetic mouse model, achieving not only the control of glucose blood levels but also the normalization of pancreatic histology and function, preserving the endogenous production of insulin.
The use of the same technology in investigational mouse models of multiple sclerosis demonstrates clinical benefits by direct delivery of the engineered hematopoietic and progenitor stem cells into the central nervous system.

Type 1 diabetes

Type 1 diabetes is a severe autoimmune disorder, which mostly affects children, characterized by selective and aggressive destruction of insulin-producing β-cells in the pancreas by autoreactive T cells. Estimated worldwide T1D prevalence is about 10% along with an incidence equal to 15 per 100,000 people, showing a clear and significant increasing trend over years. Complications of poorly managed type 1 diabetes can severely affect many organs, including heart and circulation, kidney, eye, gastrointestinal tract, and central and peripheral nervous system. In addition, the psychological impact caused by the disease is very relevant, affecting lifestyle and daily life on patients and families. Injections of insulin – either via subcutaneous injection or insulin pump – are necessary for those living with type 1 diabetes because it cannot be treated by diet and exercise alone. Insulin dosage is adjusted considering food intake, blood glucose levels and physical activity, with the goal to normalise glucose blood levels to avoid long-term complications. However, most patients do not achieve an optimal control of blood sugar, albeit the availability of new automated devices for insulin administration. Therefore, insulin is lifesaving, but it is not a solution. Altheia Science’s approach aims at exploiting the physiological control of autoimmunity by hematopoietic stem and progenitor cells restoring PD-L1 expression, thus enabling the eradication of auto-reactive T cells and preserving the pancreatic β-cell function. This may induce either a more favourable control of the disease or tolerance, reducing or abrogating the need of exogenous insulin.

Type 1 diabetes

Type 1 diabetes is a severe autoimmune disorder, which mostly affects children, characterized by selective and aggressive destruction of insulin-producing β-cells in the pancreas by autoreactive T cells. Estimated worldwide T1D prevalence is about 10% along with an incidence equal to 15 per 100,000 people, showing a clear and significant increasing trend over years. Complications of poorly managed type 1 diabetes can severely affect many organs, including heart and circulation, kidney, eye, gastrointestinal tract, and central and peripheral nervous system. In addition, the psychological impact caused by the disease is very relevant, affecting lifestyle and daily life on patients and families. Injections of insulin – either via subcutaneous injection or insulin pump – are necessary for those living with type 1 diabetes because it cannot be treated by diet and exercise alone. Insulin dosage is adjusted considering food intake, blood glucose levels and physical activity, with the goal to normalise glucose blood levels to avoid long-term complications. However, most patients do not achieve an optimal control of blood sugar, albeit the availability of new automated devices for insulin administration. Therefore, insulin is lifesaving, but it is not a solution. Altheia Science’s approach aims at exploiting the physiological control of autoimmunity by hematopoietic stem and progenitor cells restoring PD-L1 expression, thus enabling the eradication of auto-reactive T cells and preserving the pancreatic β-cell function. This may induce either a more favourable control of the disease or tolerance, reducing or abrogating the need of exogenous insulin.

Multiple sclerosis

Multiple sclerosis is a severely debilitating autoimmune disease caused by the degeneration and disruption of the myelin sheaths that surround axons of the brain and spinal cord. Myelin loss is associated to neural inflammation, axonal loss, and formation of scar tissue in the white matter, leading to a wide spectrum of neurological symptoms, including fatigue, spasticity, functional loss, and pain. The estimated worldwide number of people with multiple sclerosis has increased to 2.8 million in 2020 with a global prevalence of about 36 per 100,000 people. In most cases, the diagnosis occurs between 20 and 50 years of age, and the most common symptoms include fatigue, visual disturbances, numbness and tingling, muscle spasms, stiffness and weakness, mobility problems, pain, and problems with thinking, learning, and planning. Treatments for MS mainly target the management of symptoms and attempt to interrupt the damage to myelin sheets, and include anti-inflammatory or immuno-modulatory drugs that, given the chronic nature of the disease, expose the patient to serious side effects, with significant impact on their quality of life. Clinical patterns of appearance and progression of symptoms significantly vary, and about 10-15% of patients experience the primary progressive form of multiple sclerosis. In these patients, the direct administration of PD-L1-expressing hematopoietic stem and progenitor cells into the central nervous system may dampen the autoimmune mechanism at the basis of myelin disruption, inducing a significant clinical benefit.

 

Novel tumour-specific antigens to target liquid tumours

 

Altheia Science has developed a novel immunotherapy approach based on chimeric antigen receptor (CAR)-T cell technology using autologous cells for the treatment of myeloid disorders. This is achieved through the identification, via an innovative in silico discovery strategy, of new antigenic determinants specifically expressed on tumor cells that serve as tumor antigens. The approach involves engineering the patient’s T cells to express a specific CAR capable of selectively recognizing and eliminating tumor cells. Most importantly, the antigen expression is restricted to leukemic cells, sparing healthy cells and tissues, thus predicting a highly safe profile. Through an extensive preclinical program, Altheia Science has generated solid safety and efficacy data in animal disease models and patient-specific animal models, where the selected CAR-T cell constructs induce a significant increase in survival, along with rapid elimination of leukemic cells in the absence of in vitro and in vivo hematopoietic toxicity. The first clinical indication of this program is acute myeloid leukemia, a severe liquid tumour with highly unmet clinical need affecting children and adults.

Acute myeloid leukemia

Leukemia is a cancer of the blood, deriving from healthy hemopoietic stem cells or progenitors that change and grow out of control due to gene mutations and chromosome rearrangements. Acute myeloid leukemia is a bone marrow stem cell cancer that arises from the unbridled and rapid proliferation of clonal hematopoietic cells, interfering with the production of normal blood cells. Unlike chronic leukemia, acute leukemia develops quickly and is a severe life-threatening disease that needs immediate treatment. This can lead to a variety of symptoms, including fatigue, weakness, shortness of breath, frequent infections, anemia, easy bruising or bleeding and death.

The incidence of acute myeloid leukemia increases with age and is more commonly diagnosed in older adults with an average age of diagnosis around 68 years old. The incidence rate varies based on several factors such as sex, race, and geography. Worldwide, the estimated annual incidence of AML has increased gradually in the past 28 years (from 64/1000 in 1990 to 120/1000 new diagnoses in 2017). In children the estimated rate of 0.6-1.2 cases per 100,000 children per year, with infants younger than two years old and adolescents having the highest incidence and the more life-threatening forms. Despite the great advances in discovering new therapeutic approaches for many types of malignancies, acute myeloid leukemia remains nowadays a challenge for onco-hematology researchers, with an overall survival ranging between 50 and 74% at 8 years from diagnosis in children and between 15 and 45% in adults. The most successful treatment for acute myeloid leukemia depends on the results of the first treatment, with systemic chemotherapy being the primary treatment, which is delivered through the bloodstream to destroy cancer cells, usually by ending the cancer cells’ ability to grow and divide. Hematopoietic stem cell transplantation is recommended as consolidation therapy in both children and adult patients, in whom cytogenetic or molecular studies predict a poorer prognosis with only chemotherapy. Most recently, novel targeted therapies are also used to target leukemia’s specific genes, proteins that contributes to the growth and survival of the leukemia, specifically in adult patients. This type of treatment is preferred because it blocks the growth and spread of leukemia cells while limiting the damage to healthy cells. Targeted therapies are frequently used to treat metastatic cancer or relapses and have been shown to achieve an effective tumor control for several months. However, these rarely induce a durable treatment response, mostly due to the emergence of aggressive drug-resistant clones. Thus, acute myeloid leukemia, which is the most common leukemia diagnosed in adults, still represents the paradigm of resistance to front-line therapies in hematology and it is an indication with highly clinical unmet needs. Although multiple disease-candidate tumour associated antigens have been identified, most are also expressed by normal hematopoietic stem and progenitor cells, greatly limiting their efficacy along with exposing the patient to severe toxicity. Therefore, the poor evidence of benefit is often accompanied by evidence of toxicity. The newly identified tumour-specific antigens potentially possess the ability to overcome these clinically relevant limitations.

Multiple sclerosis

Multiple sclerosis is a severely debilitating autoimmune disease caused by the degeneration and disruption of the myelin sheaths that surround axons of the brain and spinal cord. Myelin loss is associated to neural inflammation, axonal loss, and formation of scar tissue in the white matter, leading to a wide spectrum of neurological symptoms, including fatigue, spasticity, functional loss, and pain. The estimated worldwide number of people with multiple sclerosis has increased to 2.8 million in 2020 with a global prevalence of about 36 per 100,000 people. In most cases, the diagnosis occurs between 20 and 50 years of age, and the most common symptoms include fatigue, visual disturbances, numbness and tingling, muscle spasms, stiffness and weakness, mobility problems, pain, and problems with thinking, learning, and planning. Treatments for MS mainly target the management of symptoms and attempt to interrupt the damage to myelin sheets, and include anti-inflammatory or immuno-modulatory drugs that, given the chronic nature of the disease, expose the patient to serious side effects, with significant impact on their quality of life. Clinical patterns of appearance and progression of symptoms significantly vary, and about 10-15% of patients experience the primary progressive form of multiple sclerosis. In these patients, the direct administration of PD-L1-expressing hematopoietic stem and progenitor cells into the central nervous system may dampen the autoimmune mechanism at the basis of myelin disruption, inducing a significant clinical benefit.

Novel tumour-specific antigens to target liquid tumours

 

Altheia Science has developed a novel immunotherapy approach based on chimeric antigen receptor (CAR)-T cell technology using autologous cells for the treatment of myeloid disorders. This is achieved through the identification, via an innovative in silico discovery strategy, of new antigenic determinants specifically expressed on tumor cells that serve as tumor antigens. The approach involves engineering the patient’s T cells to express a specific CAR capable of selectively recognizing and eliminating tumor cells. Most importantly, the antigen expression is restricted to leukemic cells, sparing healthy cells and tissues, thus predicting a highly safe profile. Through an extensive preclinical program, Altheia Science has generated solid safety and efficacy data in animal disease models and patient-specific animal models, where the selected CAR-T cell constructs induce a significant increase in survival, along with rapid elimination of leukemic cells in the absence of in vitro and in vivo hematopoietic toxicity. The first clinical indication of this program is acute myeloid leukemia, a severe liquid tumour with highly unmet clinical need affecting children and adults.

Acute myeloid leukemia

Leukemia is a cancer of the blood, deriving from healthy hemopoietic stem cells or progenitors that change and grow out of control due to gene mutations and chromosome rearrangements. Acute myeloid leukemia is a bone marrow stem cell cancer that arises from the unbridled and rapid proliferation of clonal hematopoietic cells, interfering with the production of normal blood cells. Unlike chronic leukemia, acute leukemia develops quickly and is a severe life-threatening disease that needs immediate treatment. This can lead to a variety of symptoms, including fatigue, weakness, shortness of breath, frequent infections, anemia, easy bruising or bleeding and death.

The incidence of acute myeloid leukemia increases with age and is more commonly diagnosed in older adults with an average age of diagnosis around 68 years old. The incidence rate varies based on several factors such as sex, race, and geography. Worldwide, the estimated annual incidence of AML has increased gradually in the past 28 years (from 64/1000 in 1990 to 120/1000 new diagnoses in 2017). In children the estimated rate of 0.6-1.2 cases per 100,000 children per year, with infants younger than two years old and adolescents having the highest incidence and the more life-threatening forms. Despite the great advances in discovering new therapeutic approaches for many types of malignancies, acute myeloid leukemia remains nowadays a challenge for onco-hematology researchers, with an overall survival ranging between 50 and 74% at 8 years from diagnosis in children and between 15 and 45% in adults. The most successful treatment for acute myeloid leukemia depends on the results of the first treatment, with systemic chemotherapy being the primary treatment, which is delivered through the bloodstream to destroy cancer cells, usually by ending the cancer cells’ ability to grow and divide. Hematopoietic stem cell transplantation is recommended as consolidation therapy in both children and adult patients, in whom cytogenetic or molecular studies predict a poorer prognosis with only chemotherapy. Most recently, novel targeted therapies are also used to target leukemia’s specific genes, proteins that contributes to the growth and survival of the leukemia, specifically in adult patients. This type of treatment is preferred because it blocks the growth and spread of leukemia cells while limiting the damage to healthy cells. Targeted therapies are frequently used to treat metastatic cancer or relapses and have been shown to achieve an effective tumor control for several months. However, these rarely induce a durable treatment response, mostly due to the emergence of aggressive drug-resistant clones. Thus, acute myeloid leukemia, which is the most common leukemia diagnosed in adults, still represents the paradigm of resistance to front-line therapies in hematology and it is an indication with highly clinical unmet needs. Although multiple disease-candidate tumour associated antigens have been identified, most are also expressed by normal hematopoietic stem and progenitor cells, greatly limiting their efficacy along with exposing the patient to severe toxicity. Therefore, the poor evidence of benefit is often accompanied by evidence of toxicity. The newly identified tumour-specific antigens potentially possess the ability to overcome these clinically relevant limitations.