🧫 What is Cell Therapy?

Cell therapy involves the transplantation of living cells into the human body to repair or replace damaged tissue, regulate immune function, or restore organ function. Depending on the cell type and treatment goals, cell therapy includes stem cell therapy, immune cell therapy, and autologous or allogeneic cell-based approaches.

🧬 Cancer Immunotherapy

Applied Technology：

• CIK Therapy (Cytokine-Induced Killer cells)
• TIL Therapy (Tumor-Infiltrating Lymphocytes)
• CAR-T Cell Therapy (Chimeric Antigen Receptor T cells)

• Cancers Treated:

  • Blood cancers (e.g., leukemia, lymphoma) — CAR-T is most advanced

  • Solid tumors (e.g., melanoma, lung cancer, gastric cancer) — TIL and CIK in clinical use

• Mechanism: Enhances T cells' ability to recognize and kill cancer cells through targeted immune activation

🧫 什麼是細胞療法？

細胞療法是指將活細胞移植到人體內，以修復、取代受損組織或調節免疫系統功能的醫療技術。根據使用的細胞種類與目的，可分為多種形式，包含幹細胞療法、免疫細胞療法、自體或異體細胞治療等。

🧬 癌症免疫細胞療法

• 代表技術：CAR-T 細胞療法（嵌合抗原受體T細胞）、TIL（腫瘤浸潤淋巴細胞）療法、CIK療法

• 主要應用癌別：

  • 血癌類（如急性淋巴性白血病、淋巴瘤）→CAR-T最成熟

  • 黑色素瘤、肺癌、胃癌等實體腫瘤→TIL、CIK應用中

• 機制：強化T細胞辨識並殺死腫瘤細胞，屬於個人化的免疫療法

⚠️ 注意事項與限制

• 多數細胞療法仍屬臨床試驗階段，需經過嚴格審查與專業醫師評估。

• 安全性與長期療效仍需更多證據，部分療法尚未取得正式藥證。

• 不可輕信未經核可的「細胞治療旅遊」或非法治療，須選擇合格醫療機構。

Chimeric antigen receptor T-cell therapy (CAR-T cell therapy) is an advanced gene-modified immunotherapy. Below is an overview of its mechanism, manufacturing process, approved products, main clinical indications, efficacy and risks, and development challenges with future trends.

1. Definition and Mechanism of Action

CAR-T cells are patient-derived T cells that have been genetically engineered to express a chimeric antigen receptor (CAR) on their surface. This receptor enables them to directly recognize and bind a specific antigen on tumor cells. Upon antigen binding, CAR-T cells become activated, proliferate, and release cytotoxic molecules that selectively kill antigen-bearing cancer cells, while also amplifying the overall immune response .

2. Manufacturing and Treatment Process

1. Leukapheresis: Collection of peripheral blood mononuclear cells from the patient to isolate T cells.

2. Genetic Transduction: Introduction of the CAR gene into T cells using viral vectors (typically retroviral or lentiviral).

3. Expansion: Ex vivo proliferation of the engineered CAR-T cells under controlled culture conditions, which usually takes several weeks.

4. Lymphodepletion: Administration of lymphodepleting chemotherapy to the patient to create "space" for the infused CAR-T cells.

5. Infusion: Return of the expanded CAR-T cells to the patient, where they seek out and destroy tumor cells .

3. Approved CAR-T Products

• Tisagenlecleucel (Kymriah): Indicated for relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) and large B cell lymphoma.

• Axicabtagene ciloleucel (Yescarta): Approved for relapsed/refractory large B cell lymphoma, follicular lymphoma, and other B cell malignancies.

• Lisocabtagene maraleucel (Breyanzi): For various relapsed/refractory non-Hodgkin lymphomas, including diffuse large B cell lymphoma and follicular lymphoma .

• Idecabtagene vicleucel (Abecma) and Ciltacabtagene autoleucel (Carvykti): Targeting BCMA for multiple myeloma.

• Tecartus: Indicated for relapsed/refractory mantle cell lymphoma.

In June 2025, the U.S. FDA removed the REMS (Risk Evaluation and Mitigation Strategy) requirements for these CAR-T therapies, retaining only enhanced labeling and warnings to streamline clinical use and broaden patient access.

4. Main Clinical Indications

• Hematologic Malignancies:

  • B cell acute lymphoblastic leukemia (B-ALL)

  • Diffuse large B cell lymphoma (DLBCL)

  • Follicular lymphoma, mantle cell lymphoma (MCL)

  • Multiple myeloma (BCMA-targeted CAR-T) .

• Solid Tumors (Clinical Trials): CRISPR-edited CAR-T cells targeting breast, colorectal, and ovarian cancers have shown high efficacy and reduced toxicity in animal models and are expected to enter human trials within five years .

5. Efficacy and Risks

• Efficacy: Complete remission rates of 40–90% in relapsed/refractory hematologic cancers, with many patients achieving durable remissions.

• Major Risks:

  • Cytokine Release Syndrome (CRS): Manifests as high fever, hypotension, and organ dysfunction; requires prompt supportive care.

  • Neurotoxicity: Includes confusion, aphasia, and seizures; generally reversible.

  • B cell Aplasia: If targeting CD19, normal B cells may be depleted, necessitating immunoglobulin replacement.

Careful monitoring and management of these toxicities are essential to maximize safety and efficacy .

6. Challenges and Future Trends

1. Solid Tumor Barriers: Immunosuppressive tumor microenvironment, antigen heterogeneity, and poor T cell infiltration hamper efficacy in solid tumors.

2. Antigen Escape: Tumor cells may downregulate or mutate target antigens; bispecific or switchable CAR designs are in development to mitigate this.

3. Allogeneic ("Off-the-Shelf") CAR-T: Using healthy donor T cells to create a universal CAR-T product could reduce costs and accelerate availability.

4. Smart Control Systems: Inducible expression systems, genetic circuits, or small-molecule switches aim to fine-tune CAR-T activity and persistence, improving safety and tolerability.

With advances in gene editing, nanotechnology, and synthetic biology, CAR-T cell therapy is poised to overcome current limitations, broaden its indications, and become a standard option for a wider patient population.

嵌合抗原受體 T 細胞療法（CAR-T 細胞療法）是一種先進的基因改造免疫療法，以下分段介紹其機制、製備流程、已獲批准的產品、主要臨床適應症、治療成效與風險，以及發展挑戰與未來趨勢。

1. 定義與作用機制

CAR-T 細胞是在患者自身的 T 細胞上，基因工程引入一段融合抗原受體（Chimeric Antigen Receptor, CAR）的 DNA，使之能直接識別並結合腫瘤細胞表面的特定抗原。當 CAR-T 細胞與目標抗原結合後，會被激活、增殖並釋放細胞毒素，專一性地殺死帶有該抗原的癌細胞，同時促進整體免疫反應，達到治療效果。

2. 製備與治療流程

1. 白血球採集（Leukapheresis）：從患者外周血分離出 T 細胞。

2. 基因轉導：利用病毒載體（通常為逆轉錄病毒或慢病毒）將 CAR 基因導入 T 細胞。

3. 體外擴增：在細胞培養條件下增殖改造後的 CAR-T 細胞，通常需數週時間。

4. 淋巴去plete化：患者先接受化療以消除部分免疫細胞，為 CAR-T 細胞創造增殖空間。

5. 回輸（Infusion）：將擴增後的 CAR-T 細胞回輸到患者體內，開始獵殺腫瘤細胞。

3. 已獲准的 CAR-T 產品

截至目前，美國 FDA 已批准多款 CAR-T 細胞療法，包括：

• Tisagenlecleucel（Kymriah）：適用於復發或難治性 B 細胞急性淋巴性白血病與大細胞 B 細胞淋巴瘤。

• Axicabtagene ciloleucel（Yescarta）：用於復發或難治性大細胞 B 細胞淋巴瘤、濾泡性淋巴瘤等。

• Lisocabtagene maraleucel（Breyanzi）：治療多種復發／難治性非何杰金淋巴瘤，含瀰漫性大 B 細胞淋巴瘤與濾泡性淋巴瘤。

• Idecabtagene vicleucel（Abecma） 與 Ciltacabtagene autoleucel（Carvykti）：針對多發性骨髓瘤之 BCMA 抗原。

• Tecartus：適用於難治性套細胞淋巴瘤等。

2025 年 6 月，美國 FDA 進一步取消了這些 CAR-T 療法的 REMS（風險評估與緩解策略）要求，僅保留加強標示與警語，以簡化臨床使用流程並擴大病患可及性。

4. 主要臨床適應症

• 血液腫瘤：

  • B 細胞急性淋巴性白血病（B-ALL）

  • 瀰漫性大 B 細胞淋巴瘤（DLBCL）

  • 濾泡性淋巴瘤、套細胞淋巴瘤（MCL）

  • 多發性骨髓瘤（MM；抗 BCMA CAR-T）。

• 實體腫瘤（臨床試驗中）：近期研究利用 CRISPR 基因編輯改造的 CAR-T，針對乳癌、結腸癌、卵巢癌等固態腫瘤，已在動物模型中展示極高療效並降低毒性，預計 5 年內進入人體試驗。

5. 治療成效與風險

• 成效：對於復發或難治性血液腫瘤，首次完全緩解率可達 40–90% 不等，不少患者獲得長期緩解。

• 主要風險：

  • 細胞因子釋放症候群（CRS）：最常見且嚴重，可表現為高熱、低血壓、器官功能障礙，需積極支持治療。

  • 神經毒性：包括譫妄、失語、癲癇樣發作等，通常可逆。

  • B 細胞缺乏：若 CAR 目標為 CD19，正常 B 細胞亦可能被清除，需補充免疫球蛋白。
    持續監測與管理風險是確保療效與安全的關鍵。

6. 挑戰與未來趨勢

1. 固態腫瘤阻礙：腫瘤微環境抑制、抗原異質性與實體腫瘤穿透率低，使得 CAR-T 治療實體腫瘤面臨挑戰。

2. 抗原逃逸：腫瘤可下調或突變抗原，導致 CAR-T 失效。雙特異性 CAR／可拆卸 CAR 設計正被開發，以減少逃逸風險。

3. 現成即用（Allogeneic）CAR-T：使用健康供體 T 細胞製備的「庫存」CAR-T，有望降低成本並加速供應。

4. 智慧控制系統：利用可誘導表達、基因迴路或小分子開關，精準調控 CAR-T 活性與半衰期，提升安全性和耐受性。

隨著基因編輯、納米技術與合成生物學的進步，CAR-T 細胞療法有望跨越現有限制，擴大適應症，成為更廣泛人群的標準治療選擇。

Cytokine-Induced Killer (CIK) cell therapy is an ex vivo–induced and expanded immunotherapy in which a patient's (or donor's) mononuclear cells are cultured with cytokines to generate highly cytotoxic CD3⁺CD56⁺ cells, then reinfused to enhance antitumor immunity. Below is an overview of its definition and history, mechanism of action, manufacturing process, clinical applications, efficacy and safety, and challenges with future directions.

1. Definition & History

CIK cells were first described by Schmidt-Wolf et al. in 1991 and entered early cancer trials in 1999. They exhibit characteristics of both T cells and natural killer (NK) cells, combining potent, non–MHC-restricted cytotoxicity with relatively low toxicity.

2. Mechanism of Action

Peripheral blood or cord blood mononuclear cells are cultured sequentially with interferon-γ, anti-CD3 antibody, IL-1, and IL-2, yielding a large population of CD3⁺CD56⁺ "CIK" cells. These cells recognize and lyse a broad spectrum of tumor targets—including lines resistant to conventional NK or LAK cells—primarily via the perforin/granzyme pathway.

3. Manufacturing Process

1. Cell Collection: Harvest peripheral blood mononuclear cells (PBMCs) from patient or healthy donor (or cord blood).

2. Cytokine Induction: Culture PBMCs with IFN-γ for 24 hours, then add anti-CD3 antibody and IL-2, continuing culture for 14–21 days to expand CD3⁺CD56⁺ cells.

3. Quality Control: Assess phenotype (CD3⁺CD56⁺ percentage), sterility (bacterial/mycoplasma), and endotoxin levels.

4. Infusion: Administer the qualified CIK cell product back to the patient, optionally in combination with chemotherapy, radiotherapy, or targeted agents.

4. Clinical Applications

• Solid Tumors: Adjuvant CIK therapy in colorectal, hepatocellular, pancreatic, and ovarian cancers has shown reduced recurrence and improved survival in multiple trials.

• Hematologic Malignancies: In acute leukemia, lymphoma, and multiple myeloma studies, CIK cells—often combined with other immunotherapies or chemotherapy—have significantly prolonged progression-free and overall survival.

• Combination Strategies: Co-administration with dendritic cells (DCs), PD-1/PD-L1 inhibitors, or chemotherapeutics can further enhance cytotoxicity and clinical benefit.

5. Efficacy & Safety

A systematic review covering 10,225 patients (1999–2019) reported that CIK therapy significantly improved median progression-free survival (mPFS), median overall survival (mOS), and overall response rate (ORR). Adverse events were generally mild—fever and fatigue—with very low rates of severe toxicity .

6. Challenges & Future Directions

1. Efficacy Variability: Yield and functionality of CIK cells vary across centers and patients; standardized manufacturing and potency assays are needed.

2. Immunosuppressive Tumor Microenvironment: Solid tumors often inhibit CIK function; future work will focus on enhancing tumor infiltration and resistance to suppression.

3. Combination Immunotherapies: Synergies with checkpoint inhibitors, CAR-T cells, or nano-formulated drugs are under investigation to broaden efficacy.

4. "Off-the-Shelf" CIK Products: Allogeneic or gene-edited CIK cell banks may lower costs and improve accessibility.

With ongoing process optimization, combinatorial regimens, and advances in genetic engineering, CIK therapy is poised to become a more universally applicable, safe, and effective cancer immunotherapy.

嵌合抗原受體 T 細胞療法（CIK，Cytokine-Induced Killer Cell Therapy）是一種體外誘導與擴增患者或供者免疫細胞，並回輸以增強抗腫瘤效能的細胞免疫療法。以下分節介紹其定義與歷史、作用機制、製備流程、臨床應用、療效與安全性，以及挑戰與未來發展。

1. 定義與歷史

CIK 細胞最早由 Schmidt-Wolf 等人在 1991 年發現，並於 1999 年開始進行癌症臨床實驗。CIK 細胞介於 T 細胞與自然殺傷細胞（NK cell）之間，兼具兩者的特性，被視為高效且低副作用的免疫效應細胞。

2. 作用機制

在體外，外周血或臍帶血單核細胞暴露於一系列細胞因子（如干擾素-γ、抗-CD3 抗體、白細胞介素-1 與白細胞介素-2）後，促使大批 CD3⁺CD56⁺ 雙陽性細胞生成。這些 CIK 細胞可非限制性地識別並裂解各類腫瘤細胞，包括對 NK 細胞或 LAK 細胞具抗性的腫瘤株，且其細胞毒性主要透過穿孔素／顆粒酶途徑實現。

3. 製備流程

1. 細胞採集：由患者或健康供者採集外周血單核細胞（PBMCs）或臍帶血單核細胞。

2. 體外誘導：將單核細胞接種於含干擾素-γ的培養基中，24 小時後加入抗-CD3 抗體與 IL-2，持續培養約 14–21 天以擴增 CIK 細胞。

3. 品質檢測：檢測細胞表型（CD3⁺CD56⁺比例）、細菌／支原體污染及內毒素含量。

4. 回輸治療：將符合品質標準的 CIK 細胞回輸至患者體內，並視情況可與化療、放療或標靶療法併用。

4. 臨床應用

• 實體瘤：多項臨床試驗顯示，CIK 療法可作為結直腸癌、肝細胞癌、胰腺癌及卵巢癌等術後輔助治療，有助降低復發風險並提高生存率。

• 血液腫瘤：在急性白血病、淋巴瘤及多發性骨髓瘤的臨床研究中，CIK 細胞與其他免疫或化療策略聯合使用，可顯著延長無進展存活期與總生存期。

• 併用策略：與樹突狀細胞（DC）、PD-1/PD-L1 抑制劑或化療藥物聯合，能增強細胞殺傷活性並改善治療成效。

5. 療效與安全性

大規模回顧（1999–2019 年，共 10,225 例患者）顯示，CIK 療法可顯著改善中位無進展存活期（mPFS）、中位總生存期（mOS）與總緩解率（ORR），且治療相關副作用以輕度發熱、乏力為主，嚴重不良事件發生率極低。

6. 挑戰與未來發展

1. 療效異質性：不同腫瘤及患者之間，CIK 細胞產量與效能差異大，需統一製備與評估標準。

2. 腫瘤免疫抑制微環境：實體瘤中免疫抑制因子與細胞可抑制 CIK 細胞功能，未來聚焦於改良細胞穿透力與抗抑制能力。

3. 聯合免疫策略：開發更多與免疫檢查點抑制劑、CAR-T 或納米藥物的協同方案，以期在更多癌種中擴大療效範圍。

4. 現成即用細胞：探索異體 CIK 或基因編輯 CIK 細胞庫，以降低成本並加速治療可及性。

隨著製程優化、聯合治療策略與基因工程技術的進步，CIK 療法有望成為更廣泛適用且高效安全的癌症免疫治療選擇。

Tumor-Infiltrating Lymphocyte (TIL) Therapy is a form of autologous cell-based immunotherapy in which a patient's own lymphocytes, isolated from their tumor microenvironment, are expanded ex vivo and reinfused to attack the tumor. Below is an overview of its definition and history, mechanism of action, manufacturing process, clinical applications, efficacy and safety, and challenges with future directions.

1. Definition & History

TIL therapy was first described by Rosenberg et al. in 1988. Tumor-infiltrating lymphocytes are T cells that have naturally migrated into the tumor tissue and therefore reflect the patient's endogenous anti-tumor immune response. Early studies demonstrated that TILs, when isolated from tumor fragments and expanded with high-dose interleukin-2 (IL-2) in vitro, could be activated to kill tumor cells with high potency.

2. Mechanism of Action

Once activated and expanded with IL-2, TILs recognize tumor cells in a non–non-MHC-restricted manner, releasing perforin and granzymes—and secreting cytokines such as interferon-γ—to induce tumor cell apoptosis. They also modulate the tumor microenvironment by secreting additional cytokines, further enhancing anti-tumor immunity.

3. Manufacturing Process

1. Tumor Harvesting: Surgical resection or biopsy is used to obtain a tumor fragment.

2. Initial Outgrowth: The fragment is minced or enzymatically digested, and lymphocytes are cultured in media containing high-dose IL-2.

3. Rapid Expansion (REP): Anti-CD3 antibody and feeder cells (e.g., irradiated PBMCs) are added to drive a 10- to 100-fold expansion over 14–21 days.

4. Quality Control & Formulation: Expanded TILs are tested for phenotype (e.g., CD3⁺, CD8⁺ frequency), cytotoxic potency, sterility, and endotoxin levels.

5. Lymphodepletion & Infusion: The patient receives a lymphodepleting chemotherapy regimen, then is infused intravenously with the TIL product, followed by supportive high-dose IL-2 to promote in vivo persistence and expansion.

4. Clinical Applications

• Melanoma: In February 2024, the FDA approved Lifileucel (brand name Amtagvi) for patients with unresectable or metastatic melanoma who progressed after PD-1 inhibitors (and, if BRAF-mutant, after BRAF/MEK inhibitors). This is the first approved TIL cell therapy for a solid tumor.

• Other Solid Tumors: Ongoing trials are evaluating TIL therapy in cervical cancer, non-small-cell lung cancer, colorectal cancer, and others, with early data showing objective responses and durable disease control in some patients.

5. Efficacy & Safety

In advanced melanoma patients treated with Lifileucel, complete response rates are approximately 20–25% and overall response rates 30–40%, with many responders maintaining benefits beyond six months. Adverse events are primarily related to the preparative lymphodepletion (e.g., cytopenias) and high-dose IL-2 support (e.g., fevers, hypotension, transient renal impairment) and require administration in specialized centers with cell therapy expertise.

6. Challenges & Future Directions

1. Complex, Costly Manufacturing: The manual, multi-step process can cost hundreds of thousands of dollars per patient.

2. Immunosuppressive Tumor Microenvironment: Factors such as TGF-β, IL-10, regulatory T cells, and myeloid-derived suppressor cells can inhibit TIL function. Strategies under investigation include genetic engineering of TILs or combining with checkpoint inhibitors to overcome suppression.

3. Automation & Standardization: Development of closed-system bioreactors and AI-driven monitoring aims to increase yield, reduce contamination risk, and hasten product release.

4. Allogeneic ("Off-the-Shelf") TIL Banks: Research is exploring the use of healthy donor or gene-edited universal TIL lines to shorten manufacturing time, lower cost, and minimize batch-to-batch variability.

With ongoing improvements in manufacturing, genetic engineering, and combination therapy strategies, TIL therapy is poised to expand its indications and become a key modality in solid tumor immunotherapy.

嵌合浸潤淋巴細胞療法（Tumor-Infiltrating Lymphocyte，TIL）是一種從患者腫瘤微環境中分離、體外擴增，再回輸以攻擊腫瘤的細胞免疫療法。以下分段介紹其定義與歷史、作用機制、製備流程、臨床應用、療效與安全性，以及挑戰與未來趨勢。

1. 定義與歷史

TIL 療法最早於 1988 年被 Rosenberg 等人發現，屬於自體細胞免疫治療的一環。TIL 指的是自然浸潤於腫瘤組織內的 T 細胞，可反映患者對腫瘤的天然免疫反應。早期研究即證實，從腫瘤組織中分離出的 TIL 具有攻擊原位腫瘤細胞的能力，並在體外經高劑量白細胞介素-2（IL-2）擴增後，能顯著提高細胞數量與活性。

2. 作用機制

體外擴增的 TIL 經高濃度 IL-2 活化後，可非限制性識別多種腫瘤抗原，並透過釋放穿孔素／顆粒酶路徑及干擾素-γ等細胞毒素殺傷腫瘤細胞。此外，TIL 能分泌多種細胞激素，改變腫瘤微環境，進一步增強抗腫瘤效應。

3. 製備流程

1. 腫瘤組織取得：利用手術或活檢取患者腫瘤塊。

2. 分離與初步培養：將腫瘤組織酶消化或切碎，分離出浸潤淋巴細胞，接種於含高劑量 IL-2 的培養基中。

3. 快速擴增（REP）：添加抗-CD3 抗體及輔助細胞（如刺激細胞株），在 14–21 天內快速擴增數十至上百倍的 TIL 細胞群。

4. 品質檢測與製劑：檢測細胞表型（CD3⁺、CD8⁺比例）、效能（細胞毒試驗）、無菌及內毒素含量。

5. 淋巴去plete化與回輸：患者接受淋巴去plete化化療，接著靜脈回輸擴增後的 TIL，並輔以高劑量 IL-2 支持，以促進其體內存活與增殖。

4. 臨床應用

• 黑色素瘤：2024 年 2 月，美國 FDA 核准 Lifileucel（商品名 Amtagvi）用於既往接受 PD-1 抑制劑（及若有 BRAF V600 突變，再加用 BRAF／MEK 抑制劑）後仍復發或轉移之不可切除黑色素瘤患者，成為首個獲批的實體腫瘤細胞療法。

• 其他實體瘤：現正於子宮頸癌、肺癌、結直腸癌等多種實體瘤進行臨床試驗，初步數據顯示部分患者能獲得腫瘤縮小或疾病穩定。

5. 療效與安全性

Lifileucel 在晚期黑色素瘤患者中，首次完全緩解率（CRR）約 20–25%，總緩解率（ORR）可達 30–40%，多數患者可維持超過 6 個月的臨床益處。常見不良反應包括淋巴去plete化後之骨髓抑制、高劑量 IL-2 引起的發熱、低血壓、腎功能暫時性下降等，須在具備細胞治療經驗的中心嚴密監護。

6. 挑戰與未來趨勢

1. 製程複雜與成本高：手工化分離、擴增流程繁瑣，單位療程成本可達數十萬美元。

2. 腫瘤微環境抑制：實體瘤中免疫抑制因子（TGF-β、IL-10）及免疫細胞抑制（Tregs、MDSCs）影響 TIL 功能，研究者正探索基因工程或聯合免疫檢查點抑制劑以克服抑制。

3. 製程自動化與標準化：未來將導入封閉式生產平台與人工智慧監控，以提升產量、降低汙染風險並加速臨床可及性。

4. 全合體（Allogeneic）TIL：嘗試利用健康供體或基因改造之通用 TIL 庫，減少取材與製備時間，並降低成本與批次差異。

隨著製程優化、基因編輯技術與聯合療法策略的成熟，TIL 療法有望擴大適應症範圍，成為實體瘤免疫治療的重要武器。