7月相聚上海，先进治疗产品创新峰会 | 第六届ATMP Shanghai Forum

MAH制度全面实施后，药品上市许可持有人须对药物研发、临床研究、生产销售、不良反应等全生命周期负责，而CMC是药品生命周期里的非常关键的一环。从药品全生命周期的角度如何看待和开展CMC工作，使其能够更好地为药品全生命周期服务，确保安全、有效的药物得以实现。

Abstract: Development of multiple iPSC-derived cell drugs is on the fast track around the globe. We at Nuwacell are investing in the utilization of iPSC-derived mesenchymal stromal cells, natural killer cells, dopaminergic neural progenitors, and pancreatic beta cells to treat human diseases. To make these cells on an industrial scale with controllable qualities, we’ve developed unique CMC for each cell product, including the clinical-grade iPSC itself. Thus far, two of our products had received regulatory clearances into Phase I clinical trials in China.

- CMC of clinical-grade iPSC

- CMC and non-clinical studies of iPSC-derived MSC

- CMC and non-clinical studies of iPSC-derived NK cells

- CMC and non-clinical studies of iPSC-derived imDAP

Abstract: Engineered T cells have attracted substantial attention in recent years as an emerging therapy for hematological and non-hematological malignancies. Despite the rapid and robust clinical responses, unexpected toxicity, such as cytokine release syndrome, still remains a major concern in this therapy. Moreover, the intrinsic ability of tumors to evade immune responses could lead to treatment failure especially in patients with solid tumors. These obstacles together highlight a need to improve current Engineered T therapy. Exosomes are small extracellular vesicles secreted by almost all cell types and have the capability of trafficking cargos to mediate many physiological，pathophysiological processes. Therefore, researchers have been trying to utilize exosomes as highly effective carriers to deliver various therapeutic agents to target cells. We reported that Engineered immune cells release extracellular vesicles with the stimulation of antigens, mostly in the form of exosomes that carry synthetic receptors on their surface. These exosomes express a high level of cytotoxic molecules and therefore inhibit tumor growth in an antigen-specific manner. Besides, exosomes do not express programmed cell death protein 1 (PD1), and thus could circumvent the immunosuppressive mechanism caused by tumor cells. More importantly, the administration of exosomes exhibited lower risk compared with engineered T therapy in a preclinical in vivo model of cytokine release syndrome. All these advantages of engineered immune cell derived exosomes suggest that they may be promising therapeutic agents against tumors.

Abstract: T cell receptor (TCR)-engineered T cell therapy is a promising approach for the treatment of solid malignancy, with multiple clinical trials reporting impressive responses using affinity-matured TCRs. However, artificially mutated TCRs can increase the risk of off-target toxicities due to unexpected cross-reactions, which limits the overall safety of this approach. To tackle this challenge, we have developed a novel strategy for cloning tumor-specific endogenous therapeutic TCRs from long-term surviving patients who have responded to immunotherapy. Specifically, we have identified a TCR (10F04) that is specific to human papillomavirus type 18 (HPV18) E7 and restricted to human leukocyte antigen (HLA) class II molecular from the peripheral blood of a patient with HPV-positive metastatic cervical cancer who received multiple antigens stimulating cellular therapy (MASCT) and exhibited sustained T-cell immunological responses. Upon transduction into human T cells, the 10F04 TCR demonstrated robust antitumor activity in both in vitro and in vivo models. Notably, the TCR effectively redirected both CD4 and CD8 T cells to specifically recognize tumor cells and induced multiple cytokine secretion along with durable antitumor activity. Importantly, no cross-reactivity was detected. As a result, this TCR is currently being investigated in a clinical trial for treating HPV18-positive cancers. Our approach of cloning tumor-specific and safe endogenous therapeutic TCRs from long-term surviving patients offers a promising strategy for developing safe and effective TCR-engineered T T-cell therapies for solid tumors. These findings provide important insights into the potential of HLA class II-restricted TCR-T therapy as a novel cancer treatment modality.

Abstract: In the past decade, immunotherapy has achieved unprecedented success in providing the complete remission rate of hematological tumors. Since 2017, 6 CAR-T products targeting CD19 or BCMA have been successfully marketed and approved for the treatment of hematological malignancies. However, unlike tumor infiltrated lymphocytes (TIL) therapy and TCR-T cell therapy, which have been proved for their effectiveness for treating solid tumors, CAR-T therapy has not yet demonstrated significant clinical efficacy, and there is still an unmet need to develop an HLA independent cellular therapeutic regimen for treating solid tumors with good clinical efficacy and manageable clinical side effects. Biotheus’ CAB-T is a novel cell therapy platform combining the advantages of CAR-T and using T cells as an anti-CD3 T cell engager delivery source. Here, we will present a comprehensive overview of our CAB-T programs with proof of safety and efficacy in multiple in vivo efficacy studies and investigator initiated trials (IIT).

Abstract: CD30 is a membrane protein that is constitutively overexpressed on all stages of cells in classical Hodgkin lymphoma (HL) and anaplastic large-cell lymphoma (ALCL) with minimal/negligible expression on normal cells, rendering its an ideal target for CAR-T cell therapy to treat relapsed/refractory HL/ALCL patients. Thus, we designed a new third-generation anti-CD30 CAR, and conducted a pilot study of 15 r/r HL/ACLC patients to test the efficacy and safety of CD30 CAR-T cell therapy, resulting in 93.3% ORR, 86.6% CR, and none CRS/ICNAS/CRES over grade 3. Thereby, a Phase I registered clinical trial was carried out in a classic 3 + 3 dose escalation manner to further validate the safety and efficacy of CD30 CAR-T cell therapy. Expectedly, 100% ORR and 83.3% CR were observed in median/high doses, while none Grade ≥ 3 CRS was found in all 9 patients. Taken together, these clinical studies demonstrated CD30 CAR-T cell therapy as a safe and effective treatment for relapsed/refractory CD30+ lymphoma patients.

- Advances of cell therapy products worldwide

- Cell therapy products: a pearl on the crown in pharmaceuticals industry

- Key considerations in CTP development

- Cell resource selection

- CMC in IND vs in BLA/NDA

- IIT study vs IND trial

- License-out vs in-house development

Abstract: Investigator-initiated trials (IITs) are of importance in cell and gene therapies.  However, few regulatory guidelines are available compared with those for IND trials. Recently, a draft guidance document applying to the IIT trials of somatic cell products was issued by the National Health Commission.  Here the speaker will review the newly issued draft guidance and related active or draft guidance documents dated 2019 and 2015 for cell products, and illustrate the emerging regulatory trends in IIT trials. Finally, recommendations for potential IIT sponsors will be discussed.

- Key points in the newly issued draft guidance document

- The emerging regulatory trends in IIT trials of cell products

- The relationship between IIT and IND trials from a regulatory perspective

- The dos and don’ts for potential IIT sponsors

Abstract: Antibodies as the core component of humoral immunity have been employed to develop novel biologics including cellular immunotherapy, mAbs and its derivatives for almost 50 years. As the counterpart of antibodies, TCRs as the most important functional molecules of cellullar immunity are also developed for novel therapeutic modalities including TCR-T cell therapy, TCR bispecifics, etc.. Because of unique features of TCRs, challenges and opportunities both exist in the way for successfully developing commercialized TCR based therapies. Nevertheless, what can be foreseen is that successful stories and failure examples will be recorded and people who are leading this area will be remembered in the history of drug development.

Abstract: Our armored HLA independent (Hi)-TCR-T integrates the features of TCR-T and the fourth generation CAR-T such as multi-targeting and immune regulatory factors-secreting. The Hi-TCR-T can effectively reprogram an intact TCR complex to recognize tumor surface antigens and thus induce more efficient anti-tumor responses and cause little cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) compared with classic CAR-T. The armored Hi-TCR-T cells recognize highly expressed surface antigens on tumor cells, activating all of the subunits of the complete TCR machinery to generate a broad and controlled response allowing for more potent tumor cell killing, faster migration to the tumor, and longer persistence so as to have a superior therapeutic index relative to CAR-T cells. Currently, our clinical trials are being carried out to treat hematological and solid malignancies with preliminary studies showing that the armored Hi-TCR-T outperformed CAR-T with increased anti-tumor efficacy and reduced toxicity. For example, We have been carrying out the first-in-class clinical trial of Nectin4/NKG2DL/FAP-targeted Hi-TCR-T cells secreting IL7 and CCL21 for therapy of relapsed/refractory advanced solid tumors such as non-small-cell lung cancer and liver cancer with impressive efficacy with only fever in absence of CRS and ICANS.

Abstract: CAR-T cell therapy is a revolutionary new pillar in cancer treatment. Although treatment with CAR-T cells has produced remarkable clinical responses with certain subsets of B cell leukemia or lymphoma, many challenges limit the therapeutic efficacy of CAR-T cells in solid tumors and hematological malignancies. Barriers to effective CAR-T cell therapy include severe life-threatening toxicities, modest anti-tumor activity, antigen escape, restricted trafficking, and limited tumor infiltration. In addition, the host and tumor microenvironment interactions with CAR-T cells critically alter CAR-T cell function. Furthermore, a complex workforce is required to develop and implement these treatments. In order to overcome these significant challenges, innovative strategies and approaches to engineer more powerful CAR-T cells with improved anti-tumor activity and decreased toxicity are necessary. In this presentation, we will discuss our company’s strategy for developing CAR-T cell therapies and present the results from clinical trials in the treatment of hematological malignancies, such as leukemia, lymphoma, and multiple myeloma. We will also present our recent endeavor in developing advanced CD7 CAR-T technology that overcomes fratricide for the treatment of T-cell leukemia and lymphoma. This technology was recognized as one of the ten greatest advances in Chinese Hematology in 2021.

Abstract: Autologous CAR-Ts are great, But many challenges remain. Natural Killer (NK) cells are the most common type of naturally allogeneic immune cells, and more recently, use of NK cells that naturally exclude a typical TCR and can be used off-the-shelf. NK Cells achieved Similar Initial Efficacy in BCL to that Observed with Autologous CAR-Ts and appeared to have Improved Safety. Achieving activity in solid tumors would be transformational for NK Cells and the cellular therapeutic space more broadly. Memory-Like Nk cells was identified in 2009, which showed long-lived, super-charged NK cells with enhanced ability to kill cancer cells. Cellular therapeutics have yet to reach their full potential in solid tumors. However, Wu-NK cells have several compelling features: (1) Increases cytotoxicity capacity by engaging ADCC; (2) Increased trafficking, penetration and persistence in TME through sequential dosing-coating of tumor with Ab prior to NK cell administration; (3) Potential decrease T cell rejection due to impaired T cell function in TME; (4) May salvage CPI failure as well as synergize with CPI. We view signals of activity in solid tumors as potentially transformative for the space.

Abstract: Chimeric antigen receptor T cells (CART) have been proved a powerful weapon to treat cancers. Extensive efforts are focused on improving the efficacy of CART in solid tumors. Phase I trial of IL18 secreting CART targeting CD19 showed remarkable clinical effects in patients with relapse from previous CART therapy, supporting the notion that IL18 may serve as an important tool to enhance CART potency in solid tumor. Meanwhile, the complicated process of autologous CART production is labor intensive and costly. Various approaches are being explored to optimize the clinical translation of universal CAR armored immune cell therapies, such as universal CART and iPS derived CAR-NK.  Alternatively, the process of CART production can be significantly accelerated by utilizing automatic equipment. The presentation will discuss how Truking Gene CART series achieve a streamline process of CART production:

- Automatic processing of patient blood samples to obtain PBMC

- Automatic isolation of T cells by magnetic beads simultaneously activating purified T cells

- One step continuous expansion of CART cells

- Automatic formulation of CART final product

The Truking gene CART series operate with sterile, closed and single use consumables to avoid microbe and cross contamination. The automated streamline process not only minimizes the risk of human errors during production, but also helps pharmaceutical companies to expand the manufacturing capacity for treating more patients.  

Abstact: The Sony CGX10 cell isolation system is innovative flow cytometry sorting platform specifically designed for cell and gene therapy manufacturing processes. The patented hydrodynamic design realizes gentle processing of cells in microfluidics chip, with five following advantages: "Closed system, GMP-ready, simple operation, high cell viability, and reliable data". Sony CGX10 can isolate target cells with multi-parameter labelling, regulate the composition of subsets in cell therapy products, and shorten manufacturing time to obtain various specific CAR-X products for patients, helping biomedical companies empower the next generation of CGT therapies development and help break through existing bottlenecks to achieve the best results.