T Cell Clinical Trials

Over the past decade, T cell clinical trials have increased by leaps and bounds, thanks to the tremendous success of CAR-T therapy. Currently, T cells are the most studied cell type in all cell therapy clinical trials, accounting for 45% of total clinical trials.

GM T cell clinical trial

About 77% of T cell clinical trials belong to GM cells. GM T cell clinical trials are divided into: CAR-T cells, TCR-T cells or others.

1. The first category, of course, is CAR-T therapy

63% of T cell clinical trials are CAR-T cells. At present, the target of approved CAR-T therapy is mainly CD19, but CD19 only accounts for 37%, and other targets include BCMA, CD22 and CD20. All of these targets, plus CD19, accounted for 58% of CAR-T trials, indicating that B-cell cancer indications continue to dominate . Dual-target CAR-T therapy, an idea for the treatment of blood tumors . Two different targets appear on the same cell, or two different CAR-T products are co-infused. This strategy may reduce relapse rates (by targeting and eliminating cancer cells resistant to CD19-targeted therapy) .

The unclear targets of solid tumors, insufficient T cell infiltration and the existence of tumor microenvironment make CAR-T treatment of solid tumors basically ineffective. About 24% of CAR-T clinical trials belong to solid tumors. The most common targets are GD2 (neuroblastoma and melanoma) , mesothelin (mesothelioma and ovarian, pancreatic, colon, etc.) , HER2 (metastatic breast cancer) and GPC3 (liver cancer) . Intravenous administration is the most common route of administration (75%) for CAR-T treatment of solid tumors . Of course, there are other routes of administration, such as intraperitoneal, intraventricular/intraventricular, intratumoral, intrahepatic arterial, intrapancreatic (via splenic vein or artery) , and intrathoracic administration. The design of preventing T cell exhaustion, improving targeting specificity and promoting tissue infiltration is the key to the success of CAR-T treatment of solid tumors .

1. The second type is TCR-T cells

12% of T cell clinical trials belong to TCR-T cells. About 81% of the targets in TCR-T clinical trials are unique to solid tumors. Common indications include hepatocellular carcinoma, melanoma, and squamous cell carcinoma of the head and neck. TCR-T cells are mostly autologous (88%)

The third category, genetically modified T cells . Such T cells are often genetically modified to induce the secretion of therapeutic payloads such as suicide genes, receptor expression, or cytokines. Allogeneic cells are mainly used. Such T cell subsets include Treg, TIL and Th.

NGM T cell clinical trial

About 24% of T cell clinical trials belong to NGM type T cells. NGM T cell clinical trials are divided into: virus-specific T cells (VST) , TAA-specific T cells (TAA-T) or others.

1. The first type is virus-specific T cells (VST)

VST is usually allogeneic (70%) , and cells are usually isolated from well-matched transplant donors, or from donors who have recovered from viral infection. VST is used in the treatment of cancer, transplant-related diseases and infectious diseases . VST can be used to eliminate virus-induced cancers. VST can also be used to treat viral infections that occur after hematopoietic stem cell transplantation. The most common targets are cytomegalovirus and Epstein-Barr virus . VST can also be used to treat viral infections (such as HIV and SARS-CoV-2) not associated with cancer and transplantation .

The second type is TAA-specific T cells (TAA-T)

TAA-T was predominantly autologous (74%) . NY-ESO-1, PRAME, and urinary biotin were the most common targets. TAA-T enables personalized therapy, and the product consists of a mixture of cells that treat TAAs and can be isolated directly from the patient. About 2/3 of TAA-T clinical trials are used to treat solid tumors.

Non-targeting accounts for 40% of clinical trials of NGM T cells , including various T cells without specific targets. Usually derived from peripheral blood, including TIL and Treg, etc. TILs are mainly used in the treatment of solid tumors. Treg is mainly used to treat GVHD and autoimmune diseases.

1. Stem Cell Clinical Trials

Stem cells have always been at the forefront of the clinical field of cell therapy. Currently, stem cells account for 36% of all current cell clinical trials covering 10 major indications. Cell sources for stem cell clinical trials include HSCs (44%) , MSCs (46%) , neural stem cells (2%) , bone marrow stem cells (3%) and others.

Hematopoietic Stem Cell Clinical Trials

Hematopoietic stem cells accounted for 44% of stem cell trials, mainly for hematopoietic stem cell transplantation . Most hematopoietic stem cell clinical trials (69%) are applicable to red blood cell-related diseases, and the remaining indications include solid tumors, non-malignant blood diseases related to white blood cells, immunodeficiency, autoimmune and transplant-related diseases. Most hematopoietic stem cell trials (61%) use allogeneic cells because of the need to replace the patient's malignant immune cells with healthy donor hematopoietic stem cells. Cells are usually derived from the bone marrow or umbilical cord blood of a matched donor. The advantages of autologous cell transplantation are low risk of rejection and good patient tolerance.

Indications: Tumor

The main indication was hematologic neoplasms (51%) , most using allogeneic cells (71%) . Currently, gene-modified hematopoietic stem cell (GM-HSC) therapy has not been approved by the FDA and is undergoing clinical safety and efficacy studies. Another indication is solid tumors (approximately 9%) . About 58% of clinical trials utilize autologous cells. Because in solid tumors, the goal is to boost the existing immune system. Of note, all phase 3 trials in solid tumors (26%) were for brain metastases or neuroectodermal carcinoma .

Indications: red blood cell related diseases

Indications are diseases related to red blood cells (approximately 18%) , and indications include sickle cell disease, anemia and thalassemia, etc. NGM-HSC therapy mainly used allogeneic cells (64%) , while GM-HSC therapy only used autologous cells (36%) . This is because autologous GM-HSCs can be modified in vitro to express the correct target gene sequence, resulting in cells containing functional proteins. The EU EMA approved two GM-HSC -based cell and gene therapies, Strimvelis for adenosine deaminase deficiency  (ADA-SCID) , and Zynteglo for the treatment of transfusion-dependent thalassemia.

Indications: immune-related diseases

The indication is for non-malignant blood diseases related to leukocyte and immune deficiency. In a small proportion of trials (4%) , hematopoietic stem cells were used to explore the treatment of autoimmune diseases. Indications include multiple sclerosis (MS) , systemic scleroderma and Crohn's disease. The numbers were small, but the relative proportion of late-stage trials was high.

Mesenchymal Stem Cell Clinical Trials

Mesenchymal stem cells (MSCs) account for 46% of stem cell clinical trials . Sources of MSCs include bone marrow, fat, umbilical cord Walton's jelly and placenta. Most MSCs therapies use allogeneic cells (65%) , and MSCs "off-the-shelf" products have become a future development trend. According to the key mechanism of action. MSCs clinical trials are roughly divided into two categories: tissue repair and immune modulation.

Tissue repair

About 32% of MSCs clinical trials focus on tissue repair applications . Degenerative disease is an important application direction. There are 30 trials using MSCs for osteoarthritis . JointStem , an autologous adipose MSCs product for the treatment of osteoarthritis , has demonstrated safety and preliminary efficacy. Neurodegenerative diseases are also a direction for MSCs therapy. Seven of these are for Alzheimer's disease, two are for Parkinson's disease, and three are for Huntington's disease. In addition, the indications for degenerative diseases include intervertebral disc degeneration and aging frailty . Wound repair is also another important direction of MSCs treatment , with 23 trials (8%) . Traumatic brain injury, spinal cord injury, acute kidney injury, ischemia-reperfusion injury, etc. are currently being studied .

Immunomodulation

About 49% of MSCs clinical trials focus on the treatment of immune diseases . The second largest disease for MSCs therapy is autoimmune disease (18%) , including rheumatoid arthritis (RA) , type 1 diabetes (T1DM) , multiple sclerosis (MS) , systemic lupus erythematosus (SLE) , etc. MSCs also hold promise in non-autoimmune diseases (14%) . Ongoing indications include the treatment of bronchopulmonary dysplasia, cirrhosis, acute and chronic pancreatitis, chronic obstructive pulmonary disease (COPD) and glomerulonephritis. About 13% of MSCs clinical trials are used for infectious diseases . With the COVID-19 pandemic, MSCs have entered the clinic for the treatment of SARS-CoV-2 infection, with two trials entering Phase 2/3. Remestemcel-L is a representative, initially used in children with aGvHD, and is now undergoing phase 3 clinical trials for the treatment of ARDS caused by COVID-19. About 4% of MSCs clinical trials are used to treat transplant-related diseases . Examples include the treatment of aGvHD and organ transplant rejection, especially liver, kidney and lung.

Other stem cells

Other stem cells (including neural stem cells, bone marrow stem cells, cardiac stem cells, endothelial progenitor cells, corneal limbal stem cells and multipotent adult progenitor cells, etc.) account for only 10%. The scope of application is relatively narrow. Indications for neural stem cells include astrocytoma, glioma, Parkinson's disease, retinitis pigmentosa, and spinal cord injury. Indications for lung stem cells include idiopathic pulmonary fibrosis and interstitial lung disease, retinal progenitors for retinitis pigmentosa, and multipotent adult progenitors for immune regulation.

DC and NK cell clinical trials

DC Clinical Trials

DC vaccine is a hot area of ​​clinical trials, about 93% of clinical trials are for cancer treatment , and the remaining indications include autoimmune diseases, infectious diseases and transplant-related diseases .

Most DC tests (89%) used autologous cells . Allogeneic cell indications are mainly in leukemia and liver transplantation . DC vaccine trials include routes of administration, addition of immunostimulatory molecules, and other combination drug regimens. The most common route of administration for DC vaccines is intradermal (45%) , although intravenous (22%) , subcutaneous (11%) , and intravascular (11%) injections are also used.

DCs can be administered in combination with stimulatory molecules, including growth factors (GM-CSF) , cytokines (IL-2) and monoclonal antibodies (anti-PD-1/PD-L1) , which can promote the expansion and transport of DCs to lymph nodes and activate T cells. cells and NK cells, or sensitize cancer cells to cytotoxic T cells. Common concomitant therapies include chemotherapy, other cell types (stem cells, T cells) , immunomodulators, and radiation therapy.

NK Cell Clinical Trials

In the past few years, NK cells have become more and more popular. This is attributed to the natural cytotoxicity, non-MHC restriction, and "off-the-shelf" utilization capacity of NK cells. Currently, NK cell trials account for 7% of all cell therapy trials. NK cell sources include allogeneic peripheral blood (53%) , autologous peripheral blood (27%) , NK cell lines (15%) and stem cells (5%) .

Although peripheral blood NK cells are still the main source (80%) , the number of primary isolation is small (ie, NK cells only account for 5%-10% of peripheral blood leukocytes) and in vitro expansion is difficult. Stem cell-derived cell products and cell lines are an idea that solves the problem of cell source and large-scale expansion. In general, CAR-NK cells are considered safer than CAR-T cells because NK cells survive in the body for a shorter period of time and are less likely to induce serious side effects. CAR-NK cells usually produce IFN-γ and GM-CSF, while CAR-T cells produce a set of cytokines (IL-1a, IL-2, IL-6, TNF-α, MCP-1, IL-8, IL -10, IL-15 and others) , causing cytokine release syndrome and severe neurotoxicity.

1. Cell type

NK cell assays include NK cells , CAR-NK cells, CIK, NK cell lines (NK-92) and iPSC/HSC-NK cells. The majority (66%) of NK cell assays used non-genetically modified NK cells, mainly to exploit their inherent cytotoxicity. CAR-NK therapy (12%) has achieved encouraging results due to the launch of CAR-T products . CAR-NK cell therapy for blood tumors (CD19, BCMA, and CD22) ; solid tumors (ROBO-1, PSMA, and mesothelin) ; COVID-19 (ACE-2). The other major cell class was CIK (11%) , with an NK-T hybrid cell phenotype, operating in a non-HC-restricted manner. CIK is also known as type II NKT cells. Here, it can be understood as NKT cells. The NK-92 cell line (7%) is easy to expand and transfect compared to native NK cells . Finally, iPSC/HSC-NK cells (4%) can overcome the limitation of the number of PBMC-derived NK cells.

1. Indications

Indications are mainly cancer (95%) , followed by infectious diseases (4%) . NK clinical trials account for a large proportion of blood tumors, acute/chronic myeloid leukemia (AML/CML) 21%, and lymphoma 11%. It is worth noting that there are more clinical trials of NK cell therapy for solid tumors than for blood tumors. CARs and combination therapies are often used to improve targeting and overcome malignancies such as glioblastoma . A fraction of NK cell trials (35%) adopted a strategy of co-administration or post-administration adjuvant therapy. Antibodies and cytokines were the most commonly used adjuvant treatments (29% for both) , followed by chemotherapy drugs, and combinations of these drugs.

Other Cell Clinical Trials

Mononuclear Cell Clinical Trials

Clinical trials with mononuclear cells are rare (2%) . Here mononuclear cells comprise one of the following cell populations: monocytes (11% of mononuclear tests) , macrophages (0% of mononuclear tests), BMMC (52% of mononuclear tests) and PBMCs (37% of individual nuclear tests).

The most common indications were cardiovascular disease (39%) and cancer (29%) , with some application in trauma (14%) . The majority (89%) of these trials used autologous cells. Numerous preclinical studies have used monocytes and macrophages as therapeutics, often in the treatment of cancer, autoimmune and inflammatory diseases.

Notably, monocytes were reinjected by leukapheresis followed by differentiation into DCs. Due to their high plasticity, monocytes are well suited for in vitro conditioning for inducing phenotypic changes prior to reinjection. BMMC and PBMC have also been included in clinical trials. Because they contain distinct cell populations, various factors can be secreted to promote wound healing and regeneration. Similar to monocytes/macrophages, these cells can induce phenotypic changes in vitro. It is also possible to enrich or deplete certain cell populations (such as naive T cells or B cells) in mononuclear cells .

Red blood cells and platelets

Clinical trials are also underway for intravenous infusions of blood supply products (such as red blood cells, whole blood, and platelets) . Red blood cells accounted for 2% of the total tests and platelets accounted for 0.4% of the total tests

In red blood cell clinical trials, the most common indications were blood disorders such as anemia (26%) and sickle cell disease (18%) . Red blood cell indications are also lung cancer, breast cancer and malaria infection. Notably, in 7 trials, erythrocytes (2 autologous and 5 allogeneic) were used as drug carriers to carry and deliver membrane-bound or encapsulated drugs to target sites. Administration is usually given by intravenous infusion. Platelet transfusions are used for induction of thrombocytopenia and posttraumatic coagulation. Usually, platelets are given intravenously.

Microbiology Clinical Trials

There are now 48 clinical trials in microbiology (3% of total trials) . The basic process includes: collecting microorganisms from healthy patients' feces, removing harmful components (such as viruses, pathogens) to isolate some or all specific microorganisms. It is usually given as a capsule by mouth. Although fecal microbiota transplantation (FMT) can be used in clinical treatment, it has not been developed as a drug , so there are no statistics for FMT clinical trials.

Summary

Cell therapy is one of the most cutting-edge and hottest directions in medical research today, and exciting results have been achieved. Every successful clinical trial is backed by solid basic research, which involves the biological characteristics of the cells themselves, the selection of indications, the selection of drug delivery methods, the selection of cells and the dosage of drug delivery, all of which are very critical factor for success.

If we can summarize and formulate a complete set of evaluation criteria from successful cases, we can extend it to other cell and gene therapies and promote their development. There will be challenges and obstacles in the development of anything, and we still believe that cell therapy will overcome the difficulties and become a reliable treatment modality.