Application Of Adoptive Immunotherapy In Ovarian Cancer

Figures & data

Table 1 Comparison Of Clinical Effects Of Four Ovarian Cancer Treatment Methods

Therapy	Clinical Efficacy Comparison	Reference
Surgery	1. Surgical treatment and chemotherapy are usually used in combination in clinical practice, not alone. 2. Primary surgery combined with postoperative platinum-taxane chemotherapy has been the standard therapy for advanced ovarian cancer. The progression-free and overall survival of complete resection (ideally with no macroscopic residual disease) are improved compared with so-called optimal and suboptimal debulking resection.	^Citation7
Chemotherapy	1. Chemotherapy is a milestone in the treatment of ovarian cancer because it improves the outcome in women with ovarian cancer. It can help to achieve no residual tumor (R0) after primary debulking surgery (PDS), or to treat patients by neoadjuvant chemotherapy (NACT). 2. The clinical efficacy of chemotherapy depends on various factors such as dose, choice of platinum and/or taxane, schedule, mode of administration (intravenous [IV], intraperitoneal [IP]) and so on. 3. However, some patients will have chemotherapy resistance, and many patients who are cured by chemotherapy will relapse.	^Citation8
Anti-VEGF treatment	1. Bevacizumab is the most widely studied anti-angiogenesis agent in ovarian cancer. 2. Two large phase III trials shown that chemotherapy with the addition of bevacizumab significantly improved the progression free survival (PFS) of patients. 3. However, there is also evidence that bevacizumab has toxicity and side effects such as gastrointestinal (GI) perforation, surgery and wound-healing complications, and hemorrhage. 4. Only a subset of patients will benefit from anti-angiogenic agents	^Citation9^–^Citation11
Immunotherapy	Tumor immunotherapy, such as anti-PD-L1/PD-1 therapies and adoptive therapy, have subsequently demonstrated significant anti-tumor effects. Although immunotherapy is still in its infancy in the clinical treatment of ovarian cancer, many promising preclinical experiments indicate its potential.	^Citation12^–^Citation14

Figure 1 Adoptive cell immunotherapy (ACT) approaches: After obtaining immune cells from the patient, leukapheresis is performed. Immune cells are activated after stimulation or genetical modification. Effective immune cells are expanded and then refused to the patient.

Figure 2 Effector cells for adoptive cell immunotherapy.

Abbreviations: MHC, major histocompatibility complex; NK, natural killer; LAK, lymphokine-activated killer; CIK, cytokine-induced killer; CAR, chimeric-antigen receptors; TCR, T cell receptors; TIL, tumor-infiltrating lymphocytes.

Figure 3 Four generation of CARs: The first generation contains a single-chain fragment of variable region (scFv) and CD3ζ signaling domain. Costimulatory molecules such as CD28 are added in the second generation. Third-generation CARs include more signaling domains. The fourth generation are characterized by addition of cytokine transgenes like IL-12 and IL-15.

Table 2 Current On-Going And Completed Clinical Trials On ACT In Ovarian Cancer

NCT Number	Status	Conditions	Type of Adoptive Therapy	Primary Outcome	Secondary Outcome	Adverse Events	Results	Reference
NCT3692637	Not yet recruiting	Epithelial Ovarian Cancer	Anti-Mesothelin CAR NK Cells	Occurrence of treatment-related adverse events	/	/	/	/
NCT3539406	Not yet recruiting	Recurrent Ovarian Carcinoma, Recurrent Fallopian Tube Carcinoma, Recurrent Primary Peritoneal Carcinoma	UCB-NK cells	Incidence of treatment emergent adverse events	1. In vivo lifespan and expansion of the infused UCB-NK cells 2. Measurement of in vitro cytolytic activity of infused NK cells 3. The effect of NK cell infusion on measurable disease	/	/	/
NCT0652899	Terminated	Fallopian Tube Cancer, Ovarian Cancer, Peritoneal Cavity Cancer	Allogeneic natural killer cells	Number of patients with in vivo expansion of infused allogeneic natural killer (NK) cell product	1. Number of patients per disease response 2. Median number of days to progression 3. Median overall survival number of days patients alive after treatment	Hemolysis, Edema, Death - disease progression NOS, Fatigue, Fever, Dyspnea and so on	1. None of the patients met the counting criteria in primary outcome. 2. None of the patients had complete response, but most of patients had partial response or stable disease. 3. Median number of days to progression was around 100 days. 4. The median number of days survived after treatment was 291 for patients who did not receive total body irradiation per protocol, whereas it was 171.5 for patients who receive total body irradiation	/
NCT2487693	Active, not recruiting	Ovarian Carcinoma	Autologous cytokine-induced killer cells	Recurrence-free survival	Adverse events related to CIK treatments.	/	/	/
NCT2482090	Completed	Metastatic Ovarian Cancer	TIL infusion	Number and type of reported adverse events	1. Treatment-related immune responses 2. Objective response rate 3. Overall survival (OS) 4. Progression-free survival (PFS)	/	Young TILs could be expanded to clinical numbers. Autologous tumor cells are found in TILs in more than 50% of patients. Antigen-specific TILs could be isolated and further expanded in vitro. These findings suggested that ACT with TILs could be beneficial to patients with OC.	^Citation53
NCT3287674	Active, not recruiting	Metastatic Ovarian Cancer	TIL infusion	Determine the safety of TIL therapy in combination with checkpoint inhibitors	1. Treatment-related immune responses 2. Objective response rate (ORR) 3. OS and PFS	/	/	/
NCT3412526	Recruiting	Metastatic Ovarian Cancer	TIL infusion	1. Objective tumor responses 2. Assess adverse events	1. OS and PFS 2. Response Rate (RR) 3. Quality of Life (QOL)	/	/	/
NCT3610490	Recruiting	Ovarian Carcinosarcoma, Recurrent Osteosarcoma, Recurrent Ovarian Carcinoma, Refractory Ovarian Carcinoma, etc	Autologous Tumor Infiltrating Lymphocytes MDA-TIL	ORR	1. Complete response rate (CRR) 2. Disease control rate (DCR) 3. Duration of response (DOR) 4. OS and PFS 5. Incidence of adverse events	/	/	/
NCT1883297	Recruiting	Recurrent, Platinum Resistant High Grade Serous Ovarian, Fallopian Tube, etc	Re-stimulated tumor-infiltrating lymphocytes (TILs)	Number occurrences and severity of side effects	1. Clinical response to treatment 2. Number of patients with an immunity and no immunity to the study treatment	/	/	/
NCT4025216	Not yet recruiting	Non-Small Cell Lung Cancer, Ovarian Cancer, Fallopian Tube Cancer, Triple Negative Breast Cancer, Multiple Myeloma, Pancreatic Ductal Adenocarcinoma	TnMUC1-Targeted Genetically Modified Chimeric Antigen (CAR)	1. Phase 1: Dose Identification of CART-TnMUC1 2. Phase 1a Expansion: Objective Response in platinum-resistant ovarian cancer	1. Safety, tolerability and feasibility of CART-TnMUC1 2. Preliminary anti-tumor efficacy of CART as assessed by OS, PFS, ORR, Clinical Benefit Rate, DOR and Time to Response 3. Expression of TnMUC1 4. Peripheral expansion and persistence of CART-TnMUC1 cells	/	/	/
NCT1583686	Terminated	Cervical Cancer, Pancreatic Cancer, Ovarian Cancer, Mesothelioma, Lung Cancer	Anti-mesothelin CAR transduced PBL	1. Frequency and severity of treatment-related adverse events 2. Percentage of patients who have a clinical response to treatment	In vivo survival of CAR gene-engineered cells	/	Currently, the study only obtained experimental results related to monoclonal antibodies and published articles.	^Citation113,Citation114
NCT3916679	Recruiting	Ovarian Cancer	Anti-MESO CAR-T cells	Safety measured by occurrence of study-related adverse effects	1. Overall complete remission rate 2. PFS after administration 3. Duration of CAR-positive T cells in circulation 4. Detection of PD-1 antibody in serum	/	/	/
NCT3585764	Recruiting	Ovarian Cancer, Fallopian Tube Cancer, Primary Peritoneal Carcinoma	MOv19-BBz CAR T cells	Number of study subjects with treatment-related adverse events	1. Tumor response rates 2. OS, PFS and ORR	/	/	/
NCT2830724	Recruiting	Pancreatic Cancer, Renal Cell Cancer, Breast Cancer, Melanoma, Ovarian Cancer	Anti-hCD70 CAR transduced PBL	1. Maximum tolerated cell dose (MTD) 2. Percentage of patients who have a clinical response to treatment (objective tumor regression)	1. In vivo survival of anti-hCD70 CAR transduced cells 2. Frequency and severity of treatment-related adverse events	/	/	/
NCT3814447	Recruiting	Ovarian Cancer	Anti- MESO CAR-T cells	Adverse events (AEs) and Serious adverse event (SAEs)	1. The highest concentration (Cmax), the time to reach the highest concentration (Tmax) and the area under the curve of 30 days of anti-human MESO T cells in the peripheral blood after administration 2. ORR and PFS after administration	/	/	/
NCT2541370	Unknown	Ovarian Tumor, Colorectal Cancer, Acute Myeloid and Lymphoid Leukemias, etc	Anti-CD133 CAR T cells	Occurrence of study-related adverse events	Anti-tumor responses to CART-133 cell infusions	Mild chills, Fever, Fatigue, Vomiting and Muscle soreness, etc	Currently, the study only obtained experimental results related to cholangiocarcinoma with published articles.	^Citation115
NCT1567891	Completed	Ovarian Cancer	NY-ESO-1ᶜ^259 T cells	Number of participants with adverse events related to study treatment	1. Tumor response 2. Peak persistence of modified T-cells in the peripheral blood 3. Determine functional properties and phenotype of modified T-cells from peripheral blood 4. Correlate NY-ESO-1 expression in tumor tissue before treatment with archival tumor tissue to assess impact of therapy on expression of NY-ESO-1 protein	Febrile neutropenia, Cytokine Release Syndrome, Anemia, Sinus Tachycardia, Nausea, White blood cell and neutrophil count decreased, etc	1. 5 out of 6 patients developed adverse events related to study treatment 2. No patient has a tumor response within the specified time range 3. Peak persistence of NY-ESO-1ᶜ^259 T cells in the peripheral blood is 85,862.6 copies of WPRE/mcg of genomic PBMC DNA 4. In the manufactured product and post-treatment blood, the percentage of CD4^+pentamer^+ or CD8^+pentamer^+ cells expressing LAG-3, PD-1, TIM-3 in the functionality of NY-ESO-1ᶜ^259T cells 5. Data was only collected from 2 subjects. The Archival/Baseline H scores of 2 subjects were 50/15 and 100/0 respectively.	/
NCT3159585	Recruiting	Stage IV of Ovarian Cancer, Esophageal Cancer, Bladder Carcinoma, etc	NY-ESO-1-specific TCR Affinity Enhancing Specific T Cell Therapy (TAEST16001)	The treatment-related adverse events of the patients received TAEST16001 treatment	Assess ORR, DOR, time to progress, PFS, OS and the expression of tumor markers	/	/	/
NCT3691376	Recruiting	Platinum-Resistant/Recurrent/Refractory Ovarian Carcinoma, Recurrent/Refractory Fallopian Tube Carcinoma, Recurrent/Refractory Primary Peritoneal Carcinoma	Autologous NY-ESO-1-specific CD8-positive T Lymphocytes	1. Incidence of adverse events 2. Maximum tolerated dose (MTD)	1. Immunological parameters associated with T cell persistence, bioactivity and functionality 2. Tumor response rates to treatment 3. PFS, OS and DOR 4. Appearance of target antigen/major histocompatibility complex (MHC) loss variants upon disease recurrence	/	/	/
NCT2457650	Recruiting	Ovarian Cancer, Bladder Carcinoma, Breast Cancer, Esophagus Carcinoma, Lung Cancer, etc	Anti-NY ESO-1 TCR-transduced T cells	Evaluate the safety and feasibility of the administration of anti-NY-ESO-1 TCR transduced T cells in patients with HLA-A2+ NY-ESO-1-expressing malignancies.	Determine if the treatment can result in clinical regression of malignant tumors in the patients.	/	/	/
NCT2869217	Recruiting	Ovarian Cancer, Lung Cancer, Bladder Cancer, Liver Cancer	NY-ESO-1 Specific TCR Gene Transduced Autologous T Lymphocytes (TBI-1301)	1. Safety profile 2. Recommended phase 2 (RP2D) dose TBI-1301 when administered following cyclophosphamide pre-treatment	Evidence of efficacy (i.e. anti-tumor effect) of TBI-1301	/	/	/

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