Trial Title:
An Clinical Study of NKG2D-CAR-NK Cells for the Treatment of Refractory Recurrent Multiple Myeloma
NCT ID:
NCT06379451
Condition:
Multiple Myeloma
Conditions: Official terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Study type:
Interventional
Study phase:
Early Phase 1
Overall status:
Not yet recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
NKG2D Chimeric Antigen Receptor NK Cell Injection
Description:
Administer KN1102 cell injection three times on day 0, day 7, and day 14, respectively.
Arm group label:
High dose group
Arm group label:
Low dose group
Arm group label:
Medium dose group
Other name:
KN1102 cell injection
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 time.Currently, clinical
application of CAR-T is mostly based on autologous T cell preparation, while
relapsed/refractory 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 2-3/100000, 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 recurrent/refractory MM can reach 81%, with a CR rate of
55.5% for patients and a strict complete remission (sCR) of 13.3%. 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 95.2% and a negative MRD conversion rate of
81.0%. 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
target/off 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 relapsed/refractory 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 MICA/MICB 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.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Age range from 18 to 70 years old;
2. Expected survival time>12 weeks;
3. Diagnosed as multiple myeloma through physical examination, pathological
examination, laboratory examination, and imaging;
4. Difficult to treat multiple myeloma patients;
5. Patients with recurrent multiple myeloma;
6. ALT, AST<3 times normal; Bilirubin<2.0mg/dl;
7. Quality of Life Score (KPS)>50%;
8. The patient has no serious diseases such as heart, liver, or kidney;
9. Recurrence or no remission of the disease after hematopoietic stem cell
transplantation or cellular immunotherapy;
10. Inappropriate conditions for stem cell transplantation or abandonment of
transplantation due to limitations in conditions;
11. Blood can be taken intravenously without any other contraindications for leukocyte
removal surgery;
12. Can understand and voluntarily sign a written informed consent form.
Exclusion Criteria:
1. Pregnant or lactating women, or women with pregnancy plans within six months;
2. Infectious diseases (such as HIV, active tuberculosis, etc.);
3. Active hepatitis B or hepatitis C infection;
4. Feasibility assessment screening proves that the transfection of targeted
lymphocytes is less than 10% or the amplification is insufficient (<5-fold) under
the co stimulation of CD3/CD28;
5. Abnormal vital signs and inability to cooperate with the examination;
6. Individuals with mental or psychological disorders who cannot cooperate with
treatment and efficacy evaluation;
7. Highly allergic constitution or a history of severe allergies, especially those who
are allergic to IL-2;
8. Subjects with systemic or severe local infections requiring anti infection
treatment;
9. Subjects with severe autoimmune diseases;
10. The doctor believes that there are other reasons why patients cannot be included in
treatment.
Gender:
All
Minimum age:
18 Years
Maximum age:
70 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Changzhou Second People's Hospital
Address:
City:
Changzhou
Zip:
213000
Country:
China
Contact:
Last name:
Wei Qin, doctor
Phone:
+8618796912763
Email:
qinwei19840601@163.com
Start date:
April 18, 2024
Completion date:
December 31, 2025
Lead sponsor:
Agency:
Changzhou No.2 People's Hospital
Agency class:
Other
Source:
Changzhou No.2 People's Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06379451
