Ignite Creation Date:
2024-05-06 @ 8:25 PM
Last Modification Date:
2024-10-26 @ 3:27 PM
Study NCT ID:
NCT06379451
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-04-23
First Post:
2024-04-17
Brief Title:
An Clinical Study of NKG2D-CAR-NK Cells for the Treatment of Refractory Recurrent Multiple Myeloma
Sponsor:
Changzhou No2 Peoples Hospital
Organization:
Changzhou No2 Peoples Hospital
Study Overview
Official Title:
An Exploratory Clinical Study of the Safety and Efficacy of NKG2D Chimeric Antigen Receptor NK Cell Injections for the Treatment of Efractory Recurrent Multiple Myeloma
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Multiple myeloma MM is a malignant disease characterized by the abnormal proliferation of clonal plasma cells However multiple myeloma remains an incurable disease and requires the exploration of more effective treatment methods to improve the efficacy of relapsed refractory multiple myeloma and prolong survival timeCurrently clinical application of CAR-T is mostly based on autologous T cell preparation while relapsedrefractory AML patients have undergone multiple chemotherapy treatments resulting in impaired self-T cell function which affects the efficacy and prognosis of CAR-T therapy Therefore it is necessary to find new alternative treatments NK cells are important immune cells in the body and are an important component of innate immunity Compared with CAR-T cell therapy CAR-NK cells have unique advantages in adoptive cell therapy NKG2D receptor is an activating receptor expressed on NK cells which can recognize NKG2D ligands NKG2DL expressed on tumor cells activating NK cell killing activity through NKG2D-NKG2DL interaction Therefore the investigators plan to treat relapsed multiple myeloma by infusing NKG2D-CAR-NK cells to evaluate its efficacy and safety
Detailed Description:
Multiple Myeloma MM is a malignant disease with clonal abnormal plasma cell proliferation It is the second most common malignant tumor in hematological system tumors The incidence rate is 2-3100000 and it is still incurable In recent years with the application of new drug based regimens such as proteasome inhibitors immunomodulators and anti CD38 monoclonal antibodies the remission rate of MM patients has been significantly improved and chemotherapy related toxic side effects have been reduced increasing the survival period of multiple myeloma from 2-3 years to more than 5 years Sequential autologous hematopoietic stem cell transplantation after intensified induction therapy is currently the preferred treatment strategy for patients suitable for hematopoietic stem cell transplantation For relapsed refractory MM new generation oral proteasome inhibitors monoclonal antibodies and specific cellular immunotherapy have shown good therapeutic effects However multiple myeloma is still an incurable disease and more effective treatment methods need to be explored to improve the efficacy and prolong survival time of relapsed and refractory multiple myeloma
In recent years CAR-T has achieved significant therapeutic effects in hematological malignancies Chimeric antigen receptor T cell CAR-T immunotherapy is a rapidly developing new approach to tumor adoptive immunotherapy in recent years Its main feature is to obtain T cells that recognize tumor antigen-specific receptors through genetic engineering modification and endow them with targeting killing and persistence CAR-T studies with MM antigen specificity have also been carried out and achieved good results CAR-T cell therapy has become an effective new treatment for MM with B-cell mature antigen BCMA becoming a clear target for CAR-T cell therapy BCMA CAR-T cells can recognize and kill MM cells derived from MM patients and exert anti-tumor effects in MM model mice through the perforin pathway The overall effective rate of anti mouse derived BCMA CAR-T cell therapy for recurrentrefractory MM can reach 81 with a CR rate of 555 for patients and a strict complete remission sCR of 133 However as the application time of CART cell therapy increases recurrence remains an unavoidable issue with approximately 40 of patients receiving CR still experiencing recurrence Meanwhile studies have shown that multi target CAR-T may prolong the remission period and reduce recurrence Expanding the coverage of MM cell targets and clearing poorly differentiated MM cells may further improve the efficacy of CAR-T in treating relapsed refractory MM Studies in mouse experimental models have confirmed that the combination of anti-CS1 CAR-T and anti-BCMA CAR-T has better therapeutic effects on myeloma cells than using anti-BCMA CAR-T alone Clinical trials have confirmed the use of mouse derived anti BCMA CAR-T cells combined with humanized anti CD19 CAR-T cell infusion for the treatment of relapsed and refractory MM with an ORR of 952 and a negative MRD conversion rate of 810 However with the extension of follow-up time patients gradually experience recurrence Therefore although CAR-T therapy has shown positive clinical results in the treatment of multiple myeloma recurrence remains a difficult problem to overcome and more treatment methods are needed to address this issue
Although CAR-T cells have strong tumor killing ability and specific targeted binding the problems in CAR-T therapy cannot be ignored Firstly CAR-T therapy has related toxic side effects mainly including 1 Autoimmune toxicity mainly refers to the on targetoff tumor toxic reaction CAR cells attack tumor cells while also attacking normal tissues expressing the same antigen causing damage to normal tissues 2 Cells Factor release syndrome CRS which is a non antigen-specific toxicity caused by high levels of immune activation beyond the physiological state is also the most prominent toxic response of CAR-T cell immunotherapy CRS is often accompanied by an increase in various inflammatory cytokines such as IL-2 IL-6 IL-10 TNF-a and IFN- γ Wait The clinical manifestations of CRS vary greatly with fever being the most common muscle pain nausea unstable hypotension and hypoxia frequently occurring The overall symptoms can range from mild flu like symptoms to severe life-threatening symptoms such as respiratory distress multiple organ dysfunction and even failure 3 Neurotoxicity also appeared in some subjects which is an unexpected toxic side effect that mainly includes symptoms such as blurred consciousness coma aphasia motor disorders and seizures Secondly the preparation cycle of CAR-T cells is long and not suitable for patients with rapid disease progression At present the preparation of CAR-T cells in the study population is mostly based on autologous peripheral blood collection and lentivirus transfection T cells need to undergo a series of operations such as sorting activation transfection and amplification before being reintroduced to patients which generally takes 2-3 weeks On the one hand it cannot meet the urgent treatment needs of patients with rapid disease progression and on the other hand long-term in vitro cultivation leads to excessive differentiation of CAR-T cells in vivo resulting in reduced survival proliferation and killing ability in vivo reducing therapeutic efficacy Finally the efficacy of CAR-T may be affected by early chemotherapy At present the clinical application of CAR-T is mostly prepared by autologous T cells and patients with relapsedrefractory AML have received multiple chemotherapy treatments resulting in impaired T cell function which affects the efficacy of CAR-T and patient prognosis Therefore it is necessary to seek new alternative treatments
NK cells are important immune cells in the body and an important component of innate immunity Under physiological conditions NK cell inhibitory receptors recognize MHC class I molecules widely expressed on the surface of normal tissue cells which inhibits NK cell function and prevents them from killing their own normal tissue cells In tumor tissue due to the downregulation of MHC class I molecule expression on the surface of tumor cells ligands that activate receptors such as NKp30 NKp44 NKp46 are upregulated leading to NK cell activation and ultimately killing tumor cells CAR-NK cells express CAR molecules on the surface of NK cells recognize target antigens through CAR and further activate NK cells to kill tumor cells The CAR structure of CAR-NK cells usually consists of three parts namely the extracellular antigen binding domain transmembrane domain and intracellular activation domain which is very similar to the CAR structure used in CAR-T cell therapy According to the different intracellular domains CAR structures will also be compared and validated accordingly
Compared to CAR-T cell therapy CAR-NK cells have their unique advantages in adoptive cell therapy 1 The probability of CAR-NK cells experiencing cytokine storms is low The pro-inflammatory cytokines secreted by CAR-T cells such as IL-1 and IL-6 are the main cytokines causing CRS Active CAR-NK cells typically produce TNF- α There is a significant difference between the types of cytokines produced by granulocyte macrophage colony-stimulating factor GM-CSF and T lymphocytes Clinical studies have shown that CAR-NK treatment significantly reduces the probability of cytokine storms 2 CAR-NK cells have multiple killing mechanisms that can kill tumor cells with low or no expression of target antigens reducing the recurrence of target antigen negative tumors CAR-T cells are difficult to recognize target cells with low or no expression of target antigens and these cells cannot be cleared leading to tumor recurrence CAR-NK cells not only recognize tumor surface antigens through single chain antibodies to kill tumor cells but also activate various receptor recognition ligands to kill tumor cells Such as natural cytotoxic receptors NKp46 NKp44 and NKp30 NKG2D and DNAM-1 In addition NK cells pass through Fc γ RIII CD16 induces antibody dependent cytotoxicity and multiple mechanisms combine to kill heterogeneous tumor cells thereby reducing the risk of tumor recurrence 3 Allogeneic transplantation of CAR-NK cells does not cause graft-versus-host disease GvHD When CAR-T cells in the test population are generated by healthy donors who do not match human leukocyte antigen HLA Non autogenous MHCs expressed on allogeneic CAR-T cells can induce immune rejection and cause severe hematological toxicity NK cells are innate immune cells that do not rely on MHCs molecular recognition Allogeneic CAR-NK cells do not induce GvHD production 4 NK cells come from multiple sources to meet the needs of patients whose cell quality and quantity are affected by multiple chemotherapy treatments NK cells can be obtained from human umbilical cord blood peripheral blood induced pluripotent stem cells and NK-92 cell lines For patients who have difficulty collecting sufficient cells due to multiple chemotherapy treatments multiple sources of NK cells can meet the needs of CAR-NK treatment 5 CAR-NK cells can provide timely spot type treatment NK cells are not limited by major histocompatibility complexes therefore allogeneic NK cells can be used for modification and development into off the shelf CAR-NK cell therapy For patients with rapid tumor progression timely treatment can be provided to avoid disease progression due to waiting for cell preparation
The NKG2D receptor is an activating receptor that expresses NK cell expression It can recognize the NKG2D ligand NKG2DL expressed in tumor cells and activate NK cell killing activity through NKG2D-NKG2DL interactions NKG2DL is located at different positions on chromosome 6 and belongs to two gene families including MICAMICB and ULBPs The NKG2D ligand is expressed at different levels on the surface of tumor cells or virus infected cells while it is not expressed on the surface of normal cells with over 70 of human tumor cells showing upregulation of the NKG2D ligand Our previous research has shown that the U266 myeloma cell line and over 62 of MM patients express different levels of NKG2D ligands and immune cells can mediate the killing of MM cells through the interaction between NKG2D receptors and ligands Targeted NKG2DL CAR-NK cell therapy for MM achieved good therapeutic effects in preclinical experiments At the same time 5 recurrent MM received NKG2D-CAR-NK cells without treatment-related adverse reactions dose limiting toxicity and no CRS response observed A preclinical study has shown that NKG2D-CAR-NK has a more cytotoxic effect on MM cells than simply expanded and activated NK cells providing a basis for the treatment of MM with NKG2D-CRA-NK
Therefore choosing NKG2DL as the target for treating AML has three main advantages on the one hand its specific expression on tumor cells can ensure the safety of CAR-NK drugs and avoid serious off target toxicity In addition the diversity of NKG2D ligands can to some extent avoid tumor recurrence caused by MM cell heterogeneity or single target deficiency and better maintain drug efficacy Finally NKG2DL as a therapeutic target for MM has obtained positive clinical data Therefore the investigators plan to evaluate the efficacy and safety of combined infusion of NKG2D-CAR-NK cells in the treatment of recurrent multiple myeloma The clinical data of this study can provide data support for new treatment plans for relapsed refractory MM
In recent years CAR-T has achieved significant therapeutic effects in hematological malignancies Chimeric antigen receptor T cell CAR-T immunotherapy is a rapidly developing new approach to tumor adoptive immunotherapy in recent years Its main feature is to obtain T cells that recognize tumor antigen-specific receptors through genetic engineering modification and endow them with targeting killing and persistence CAR-T studies with MM antigen specificity have also been carried out and achieved good results CAR-T cell therapy has become an effective new treatment for MM with B-cell mature antigen BCMA becoming a clear target for CAR-T cell therapy BCMA CAR-T cells can recognize and kill MM cells derived from MM patients and exert anti-tumor effects in MM model mice through the perforin pathway The overall effective rate of anti mouse derived BCMA CAR-T cell therapy for recurrentrefractory MM can reach 81 with a CR rate of 555 for patients and a strict complete remission sCR of 133 However as the application time of CART cell therapy increases recurrence remains an unavoidable issue with approximately 40 of patients receiving CR still experiencing recurrence Meanwhile studies have shown that multi target CAR-T may prolong the remission period and reduce recurrence Expanding the coverage of MM cell targets and clearing poorly differentiated MM cells may further improve the efficacy of CAR-T in treating relapsed refractory MM Studies in mouse experimental models have confirmed that the combination of anti-CS1 CAR-T and anti-BCMA CAR-T has better therapeutic effects on myeloma cells than using anti-BCMA CAR-T alone Clinical trials have confirmed the use of mouse derived anti BCMA CAR-T cells combined with humanized anti CD19 CAR-T cell infusion for the treatment of relapsed and refractory MM with an ORR of 952 and a negative MRD conversion rate of 810 However with the extension of follow-up time patients gradually experience recurrence Therefore although CAR-T therapy has shown positive clinical results in the treatment of multiple myeloma recurrence remains a difficult problem to overcome and more treatment methods are needed to address this issue
Although CAR-T cells have strong tumor killing ability and specific targeted binding the problems in CAR-T therapy cannot be ignored Firstly CAR-T therapy has related toxic side effects mainly including 1 Autoimmune toxicity mainly refers to the on targetoff tumor toxic reaction CAR cells attack tumor cells while also attacking normal tissues expressing the same antigen causing damage to normal tissues 2 Cells Factor release syndrome CRS which is a non antigen-specific toxicity caused by high levels of immune activation beyond the physiological state is also the most prominent toxic response of CAR-T cell immunotherapy CRS is often accompanied by an increase in various inflammatory cytokines such as IL-2 IL-6 IL-10 TNF-a and IFN- γ Wait The clinical manifestations of CRS vary greatly with fever being the most common muscle pain nausea unstable hypotension and hypoxia frequently occurring The overall symptoms can range from mild flu like symptoms to severe life-threatening symptoms such as respiratory distress multiple organ dysfunction and even failure 3 Neurotoxicity also appeared in some subjects which is an unexpected toxic side effect that mainly includes symptoms such as blurred consciousness coma aphasia motor disorders and seizures Secondly the preparation cycle of CAR-T cells is long and not suitable for patients with rapid disease progression At present the preparation of CAR-T cells in the study population is mostly based on autologous peripheral blood collection and lentivirus transfection T cells need to undergo a series of operations such as sorting activation transfection and amplification before being reintroduced to patients which generally takes 2-3 weeks On the one hand it cannot meet the urgent treatment needs of patients with rapid disease progression and on the other hand long-term in vitro cultivation leads to excessive differentiation of CAR-T cells in vivo resulting in reduced survival proliferation and killing ability in vivo reducing therapeutic efficacy Finally the efficacy of CAR-T may be affected by early chemotherapy At present the clinical application of CAR-T is mostly prepared by autologous T cells and patients with relapsedrefractory AML have received multiple chemotherapy treatments resulting in impaired T cell function which affects the efficacy of CAR-T and patient prognosis Therefore it is necessary to seek new alternative treatments
NK cells are important immune cells in the body and an important component of innate immunity Under physiological conditions NK cell inhibitory receptors recognize MHC class I molecules widely expressed on the surface of normal tissue cells which inhibits NK cell function and prevents them from killing their own normal tissue cells In tumor tissue due to the downregulation of MHC class I molecule expression on the surface of tumor cells ligands that activate receptors such as NKp30 NKp44 NKp46 are upregulated leading to NK cell activation and ultimately killing tumor cells CAR-NK cells express CAR molecules on the surface of NK cells recognize target antigens through CAR and further activate NK cells to kill tumor cells The CAR structure of CAR-NK cells usually consists of three parts namely the extracellular antigen binding domain transmembrane domain and intracellular activation domain which is very similar to the CAR structure used in CAR-T cell therapy According to the different intracellular domains CAR structures will also be compared and validated accordingly
Compared to CAR-T cell therapy CAR-NK cells have their unique advantages in adoptive cell therapy 1 The probability of CAR-NK cells experiencing cytokine storms is low The pro-inflammatory cytokines secreted by CAR-T cells such as IL-1 and IL-6 are the main cytokines causing CRS Active CAR-NK cells typically produce TNF- α There is a significant difference between the types of cytokines produced by granulocyte macrophage colony-stimulating factor GM-CSF and T lymphocytes Clinical studies have shown that CAR-NK treatment significantly reduces the probability of cytokine storms 2 CAR-NK cells have multiple killing mechanisms that can kill tumor cells with low or no expression of target antigens reducing the recurrence of target antigen negative tumors CAR-T cells are difficult to recognize target cells with low or no expression of target antigens and these cells cannot be cleared leading to tumor recurrence CAR-NK cells not only recognize tumor surface antigens through single chain antibodies to kill tumor cells but also activate various receptor recognition ligands to kill tumor cells Such as natural cytotoxic receptors NKp46 NKp44 and NKp30 NKG2D and DNAM-1 In addition NK cells pass through Fc γ RIII CD16 induces antibody dependent cytotoxicity and multiple mechanisms combine to kill heterogeneous tumor cells thereby reducing the risk of tumor recurrence 3 Allogeneic transplantation of CAR-NK cells does not cause graft-versus-host disease GvHD When CAR-T cells in the test population are generated by healthy donors who do not match human leukocyte antigen HLA Non autogenous MHCs expressed on allogeneic CAR-T cells can induce immune rejection and cause severe hematological toxicity NK cells are innate immune cells that do not rely on MHCs molecular recognition Allogeneic CAR-NK cells do not induce GvHD production 4 NK cells come from multiple sources to meet the needs of patients whose cell quality and quantity are affected by multiple chemotherapy treatments NK cells can be obtained from human umbilical cord blood peripheral blood induced pluripotent stem cells and NK-92 cell lines For patients who have difficulty collecting sufficient cells due to multiple chemotherapy treatments multiple sources of NK cells can meet the needs of CAR-NK treatment 5 CAR-NK cells can provide timely spot type treatment NK cells are not limited by major histocompatibility complexes therefore allogeneic NK cells can be used for modification and development into off the shelf CAR-NK cell therapy For patients with rapid tumor progression timely treatment can be provided to avoid disease progression due to waiting for cell preparation
The NKG2D receptor is an activating receptor that expresses NK cell expression It can recognize the NKG2D ligand NKG2DL expressed in tumor cells and activate NK cell killing activity through NKG2D-NKG2DL interactions NKG2DL is located at different positions on chromosome 6 and belongs to two gene families including MICAMICB and ULBPs The NKG2D ligand is expressed at different levels on the surface of tumor cells or virus infected cells while it is not expressed on the surface of normal cells with over 70 of human tumor cells showing upregulation of the NKG2D ligand Our previous research has shown that the U266 myeloma cell line and over 62 of MM patients express different levels of NKG2D ligands and immune cells can mediate the killing of MM cells through the interaction between NKG2D receptors and ligands Targeted NKG2DL CAR-NK cell therapy for MM achieved good therapeutic effects in preclinical experiments At the same time 5 recurrent MM received NKG2D-CAR-NK cells without treatment-related adverse reactions dose limiting toxicity and no CRS response observed A preclinical study has shown that NKG2D-CAR-NK has a more cytotoxic effect on MM cells than simply expanded and activated NK cells providing a basis for the treatment of MM with NKG2D-CRA-NK
Therefore choosing NKG2DL as the target for treating AML has three main advantages on the one hand its specific expression on tumor cells can ensure the safety of CAR-NK drugs and avoid serious off target toxicity In addition the diversity of NKG2D ligands can to some extent avoid tumor recurrence caused by MM cell heterogeneity or single target deficiency and better maintain drug efficacy Finally NKG2DL as a therapeutic target for MM has obtained positive clinical data Therefore the investigators plan to evaluate the efficacy and safety of combined infusion of NKG2D-CAR-NK cells in the treatment of recurrent multiple myeloma The clinical data of this study can provide data support for new treatment plans for relapsed refractory MM
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None