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May 21, 2019 / Medical Mace eMedClub / -Local May 31 to June 4, the 55th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago, Illinois, USA Held.
As the world's leading and the most influential academic organization for oncology and the most prestigious and largest academic conference in the field of clinical oncology, ASCO has always been committed to the prevention and treatment of cancer, bringing together the elites of clinical oncology research worldwide, Showing the most advanced clinical oncology research results and cancer treatment technologies in the world.Among them,there is no doubt that cancer immunotherapy will become an important topic of ASCO.
Under the heading "Developmental Immunotherapy and Tumor Immunobiology", a number of companies/institutions at home and abroad shared a total of 33 abstracts on cell therapy, including the latest clinical progress of CAR-T, TCR-T, TIL...ect.
Six pharmaceutical companies that have attracted the attention of medical doctors are as follows. We can see that CAR-T cells are still hot in the treatment of blood tumors, and a variety of cell therapy challenges solid tumors will also become the focus.
New CAR-T therapy to improve the status of blood cancer treatment
Title: The efficacy and safety of CAR19/22 T cell "cocktail" therapy in patients with refractory/recurrent B-cell non-Hodgkin's lymphoma
Abstract Number: 2534
Clinical trial information: ChiCTR-OPN-16008526
[Background]Recurrence of antigen escape has become a major challenge for long-term disease control after CD19 targeted therapy. CD19 and CD22 dual-targeted therapy have been proposed as a potential solution.
In 2016, Professor Zhou Jianfeng from Wuhan Tongji Hospital teamed up with Wuhan Bio-Raid to register an open-label, single-center and one-arm preliminary study of CAR-T cell combination therapy to evaluate adults with refractory or relapsed B-cell malignancies. Safety and effectiveness in patients.
It is worth noting that this is the first clinical study in the world to treat refractory recurrent B-cell hematologic tumors with two sequential CAR-T cell sequential reinfusions.At the annual meeting of the American Society of Blood (ASH) in 2017, it attracted widespread attention in the world.(See:ASH Annual Meeting, the voice from China, the doctor broke the news)
[Methods]From March 2016 to January 2018, a pilot study was conducted in 38 patients with refractory/recurrent B-cell non-Hodgkin's lymphoma (B-NHL) (ChiCTR-OPN-16008526). The efficacy and safety of sequential infusion of anti-CD19 CAR-T and anti-CD22 CAR-T (two single-specific third-generation CAR19/22 T-cell "cocktail therapies") were evaluated.The deadline for data collection is April 30, 2018.
[Results]At least 3 months follow-up, 26 of 36 evaluable patients received ORR, of which 18 were CR and 8 were PR.Regardless of pathological subtype, cell origin, cytogenetics, or genomic abnormalities, the ORR was consistent across different subgroups at 3 months.At the time of data cutoff, 15 of the 18 CR patients maintained their response at 3 months, and 2 of the 8 PR patients developed CR within 3 months without additional treatment.Overall, the best ORR was 83.3%, the best CR rate was 55.5%, and the best PR rate was 27.8%.The median follow-up was 5.3 months (range 0.4 to 16.2), with a median PFS of 5.8 months and no median OS (NR).
PFS in patients who were treated for the first time with relapse was superior to those who were treated with primary refractory disease or multiple relapses.It is worth noting that patients who achieved an overall response (R3m) at 3 months significantly prolonged PFS and OS compared to patients who did not.Repeat biopsy and IHC were performed in 3 of 13 patients, and no loss of CD19 or CD22 was detected.In 9 patients with IgH/MYC translocation, the median follow-up was 10.1 months, with median PFS and median OS being NR.At the time of data cutoff, 7 patients who had reached R3m maintained response, including all 4 dual lymphomas.However, in 10 patients with del(17p) or TP53 mutations, the median follow-up was 5.3 months (range 2.7 to 14.5), with a median PFS of 3.6 months and a median OS of 9.9 mos.All patients had reversible CRS, of which 21.1% were high.The incidence of neurotoxicity was 13.2%, both of which were low.
[Conclusions]The results of this study indicate that sequential infusion of CAR19/22 T cells is safe and effective for patients with B-NHL.Dual antigen targeting is a promising approach to overcome the recurrence of antigen loss after CAR-T cell therapy.The impact of genetic subtypes and clinical parameters further underscores the importance of personalized immunotherapy.
Title: Phase I Clinical Study of Humanized Alpaca Single Domain Antibody as an Antigen Recognition Domain Targeting BCMA CAR-T Cells
Abstract number: 2535
Clinical trial information: NCT03661554
[Background]Several Phase I clinical trials have shown that CAR-T cells targeting B cell mature antigen (BCMA) have the desired effect of treating relapsed/refractory multiple myeloma (MM).Researchers at PREGENE in Shenzhen have developed a single domain antibody (nanobody) as a recognition domain for CART cells (CART-BCMA).An anti-BCMA single domain antibody was extracted from alpaca with an affinity of 1.14 nM.CART-BCMA uses the 4-1BB and CD3 sputum intracellular regions as T cell activation domains.
PREGENE CART-BCMA structure chart (data source: ASH Puri Gold poster)
Using self-developed CMC processes, PREGENE's CART-BCMA products have higher affinity, better stability, lower immunogenicity and lower production costs.Thanks to this, PREGENE has reached a cooperation agreement with a pharmaceutical company in South Korea. PREGENE has authorized CART-BCMA's interest in the Korean market to become the second CAR-T product authorized by China after the Nanjing Legend.In addition, the company is simultaneously expanding business cooperation in the European and American markets.Currently, the candidate product is in the IND declaration.
[Methods]Phase I single-arm clinical study to evaluate the safety and efficacy of CART-BCMA.All RRMM patients enrolled received an average of 10 prior treatments regardless of the level of expression of BCMA on plasma cells.After a Cy (300-600 mg/m2, d-5, -4) + Flu (30 mg/m2, d-5 ~ d-3) lymphatic depletion regimen, the CART infusion dose was 2-10×10^6 CAR + cells / kg.The efficacy was evaluated according to the IMWG standard and the toxicity was graded using CTCAE 4.02.
[Results]As of December 31, 2018, 16 patients underwent autologous CART-BCMA cell infusion and were followed for at least 1 month.Many patients have M protein in their serum, but the percentage of plasma cells in the bone marrow is not high. CART cells are difficult to treat because tumor cells aggregate rather than spread in the bone marrow.Three patients were diagnosed with extramedullary disease and evaluated as PR on day 28 (tumor SPD decreased by more than 50%).There were 13 cases without extramedullary lesions, D28, ORR was 84.6% (11/13); at 10 weeks, 7 patients were evaluated, ORR was 100% (sCR/CR 42.8%, VGPR 14.3%, PR 42.8%); Five patients who reached 16 weeks, 1 had recurrence and 4 had sustained remission.Pt3 and Pt6 are shown as grade 3 or grade 4 CRS, others are shown as grade 0-2 CRS, and CRS is controllable.
[Conclusion]Compared with other reported results of targeting BCMA CART, the results of this study showed good efficacy and supported the further development of this anti-recurrent/refractory MM cell immunotherapy.
Challenge solid tumor
Title: Phase I trial of Claudin 18.2 specific chimeric antigen receptor T cells for advanced gastric cancer and pancreatic cancer
Abstract number: 2509
Clinical trial information: NCT03159819
[Background]CAR-T cell therapy is a promising method for the treatment of certain cancers, and its success in solid tumors is limited.Claudin 18.2 (CLDN 18.2) is a specific subtype of Claudin-18 in the stomach and is highly expressed in both gastric and pancreatic cancers.
Previously, CARsgen Biology and the Shanghai Cancer Institute jointly developed and demonstrated the ability of CLDN 18.2 specific CAR (CAR-CLDN 18.2) T cells to clear CLDN 18.2 positive gastric cancer xenografts without significant on-target/off- Tumor toxicity (Huang J. JNCI 2018).In August 2017, CARsgen Bio-Supported Changhai Hospital affiliated to the Naval Military Medical University launched a world-wide clinical study of gastric cancer and pancreatic cancer CAR-T cells initiated by researchers, targeting Claudin 18.2, and began recruiting patients.
[Methods]This one-arm, open-label, first-in-human first-stage pilot study (NCT03159819) studied the safety and exploration of autologous CAR-CLDN18.2 T cells. The age of enrolled patients was 18 to 70-year-old, confirmed CLDN 18.2 positive advanced gastric or pancreatic adenocarcinoma, received CAR-CLDN18.2 T cell infusion once after lymphocyte clearance pretreatment (fludarabine and cyclophosphamide, with or without nab-paclitaxel) Or more than once until the disease progresses or there is unbearable toxicity.Adverse event (AE) grades were classified according to CTCAE 4.0 and tumor response was assessed according to RECIST 1.1.
[Results]As of November 30, 2018, 12 patients with metastatic adenocarcinoma (7 cases in the stomach and 5 cases in the pancreas) were infused with CAR-positive T cells 1-5 times (0.5 - 55 × 10^8 times).There were no serious adverse events, treatment-related deaths, or severe neurotoxicity in this study.There were no grade 4 AEs except lymphocytes, neutrophils and leukopenia.The observed cytokine release syndrome (CRS) was grade 1 or 2.Of the 11 subjects, 1 (stomach adenocarcinoma) completely resolved CR, 3 (2 cases of gastric adenocarcinoma, 1 case of pancreatic adenocarcinoma) partially relieved PR, 5 cases were stable SD, and 2 cases progressed PD.The overall objective response rate was 33.3%, and the median progression-free survival (PFS) was estimated to be 130 days by the Kaplan-Meier method [95% CI (38,230)].
【Conclusion】This clinical study shows that CAR-CLDN18.2 T cell therapy is safe and well tolerated and may have a good therapeutic effect on advanced gastric and pancreatic adenocarcinoma.
Title: Safety and efficacy of repeated intrahepatic artery and intravenous infusion of ET140202, a novel anti-AFP/MHC complex T cell, in the treatment of advanced hepatocellular carcinoma
Abstract number: e14013
[Background]Despite the success in hematological malignancies, the use of CAR-T and other redirected T cell pairs is due to the lack of unique tumor antigens, the inefficient transport of CAR-T cells to tumor sites, and the presence of immunosuppressive tumor microenvironments. Immunotherapy of solid tumors remains challenging.
ET140202 is a novel T cell platform that utilizes GPC3 (phosphatidylinositol-3)-directed costimulatory domains to target AFP (alpha-fetoprotein)/MHC complexes with the aim of increasing specificity and efficacy.Here, researchers from Wuhan University People's Hospital, EUREKA, and Aon Bio reported a case study of ET140202, which had AFP+ recurrent hepatocellular carcinoma (HCC), had previously undergone surgery and two TACEs. (transcatheter arterial chemoembolization) treatment.Baseline images showed multiple nodules in the seventh segment of the right lobe and enlarged lymph nodes in the hilar region.
[Methods]From September 25, 2018 to January 29, 2019, the subjects received 2 intra-arterial infusions (ia) of ET140202 T cells at a dose of 3 × 10 ^ 6 cells / kg. Four intravenous infusions (iv) were performed at a dose of 6 x 10^6 cells/kg.Lymphocyte depletion chemotherapy was not performed prior to T cell infusion.Vital signs, blood counts and blood chemistry were monitored on days 1, 3, 7 and 14.Clinical responses were assessed at 1, 2, 3, 4, 6, 9, 12, and 24 months.
[Results] The vital signs were normal after each infusion.No treatment-related grade 2 or higher AEs were observed.Primary events that may be associated with treatment include a brief increase in AST (aspartate aminotransferase) and bilirubin at 58 days after the first infusion.Both incidents were resolved without treatment within 4 days.Subjects did not have any clinical signs of CRS or neurotoxicity.Follow-up at 1, 2, and 3 months showed that the number and size of liver nodules increased slowly over time.Follow-up at the 4th month showed that the size of the liver nodules decreased by more than 50% of the baseline and the PR was assessed according to RECIST criteria.Subjects received an increase in AFP levels after infusion, peaking at 2097 ng/mL after 55 days of the first infusion, gradually decreasing to 905 ng/mL on day 67, and increasing to 2660 ng/mL on day 2, and finally A follow-up (130 days) gradually decreased to 1235 ng/mL.
[Conclusion]Repeated infusion of ET140202 T cells via the ia and iv pathways was safe and showed early signs of efficacy after 4 months of treatment with AFP+/HLA-A2+ HCC subjects.
HRYZ BIO TECH CO
Title: Safety and efficacy of PD-1 blockade-activated multi-antigen-specific cell therapy alone or in combination with apatinib in patients with advanced solid tumors: a pooled analysis of two prospective trials
Abstract number: e14014
Clinical trial information: NCT02844881; NCT02858232
[Background]Multi-target antigen peptide autoimmune cell therapy (MASCT) can kill cancer cells by blocking PD-1 in vitro and reversing vascular endothelial growth factor (VEGF)/VEGF receptor 2 with apatinib. Mediated immunosuppression is enhanced.The study analyzed aggregated data from Phase I/II trials to assess the toxicity and efficacy of PD-1 blockade (SHR-1210)-activated MASCT (aMASCT) alone or in combination with apatinib in patients with advanced solid tumors.
[Methods]After standard treatment, aMASCT (n=32) or aMASCT combined with apatinib (500 mg qd, n=38) were used alone for patients with selected types of advanced solid tumors.The primary endpoint was a safety profile; anti-tumor response, progression-free survival, and overall survival were secondary endpoints.Circulating regulatory T cells (Tregs) were quantified before and after aMASCT infusion.
[Results]AMASCT and aMASCT combined with apatinib group had treatment-related adverse events in 18/32 (56.3%) and 25/38 (65.8%) patients, respectively; fever and chills were the most common adverse events.No serious adverse events were reported, and apatinib did not increase the toxicity associated with immunotherapy.Compared with the aMASCT group, the objective response rate of aMASCT combined with apatinib group was improved (34.2% and 18.8%, respectively); PFS was longer (median, 6.0 and 4.5 months, respectively, P<0.05). However, the OS did not improve (median 10.0 and 8.2 months, P=0.098).Multivariate analysis showed that two or more aMASCT treatment cycles were independent prognostic factors for PFS and OS.After one cycle of aMASCT treatment, circulating Tregs decreased in both groups (P<0.05).
【Conclusion】AMASCT combined with apatinib is safe and effective in the treatment of advanced solid tumors, which may be beneficial for patients with advanced solid tumors.
Title: Phase Ia clinical trial of adoptive transfer of peripheral blood-derived cytotoxic T lymphocytes targeting individual nascent antigens in patients with advanced solid tumors
Abstract number: e14025
Clinical trial information: NCT02959905
BACKGROUND:Adoptive transfer of tumor-infiltrating lymphocytes (TILs) targeting neonatal antigens mediates complete and long-lasting regression of solid tumors.However, the limited number of fresh tumors hinders the use of TILs.Based on the nascent antigen-specific T cells that appear in the circulation, Ginoin Biosciences conducted a phase Ia clinical trial in which patients with advanced solid tumors were treated with adoptive transfer of peripheral blood-derived cytotoxic T lymphocytes (CTLs).
[Methods]This Phase Ia clinical trial was designed to detect the safety and objective response of CTL treatment targeting new antigens in individuals.Patients underwent apheresis at -25, 0, 25, 50, 85, and 110 days, then CD8+ T cells were isolated from peripheral blood, co-cultured with autologous dendritic cells, and induced with neonatal antigenic peptides. A CTL for infusion targeting neonatal antigen is produced.On days 0, 25, 50, 85, 110, and 135, patients received CTLs, respectively, and CTLs were prepared 25 days earlier.?Patients were evaluated on days 55 and 140 and were followed up for 32 weeks from day 150.The survival of infused CTLs was analyzed based on the sequence of the CDR3 region of the T cell receptor.
TSA-CTL technical process (Source: GENOM)
[Results]As of October 16, 2018, 10 patients were enrolled, and 9 patients received infusion of 0.35-4×10^8 CTLs for 1-6 times, including 8 cases of metastatic melanoma and 1 case of colorectal cancer. Seven of the 10 subjects were evaluated, including 1 PR, 1 iPR (PR according to iRECIST), 3 SD, 2 PD, ORR 28.57, and disease control rate 71.4%. All subjects were safe tolerated and the highest level of adverse events associated with adoptive cell metastasis was grade 2.Neonatal antigen-specific CTLs persisted for 140 days in the peripheral blood of 2 PR or iPR subjects.
[Conclusion]Adoptive transfer of peripheral blood-derived CTLs targeting targeted neonatal antigens is safe (at the current dose in this study) and has initial efficacy.
The above abstract text reference: