Cancer Immunotherapy Notes

Learning Outcomes

• It is possible to target cancer by manipulating the immune system. (可以通過縱免疫系統來靶向癌症。)

• Therapeutic strategies and clinical examples: (治療策略和臨床範例：)

  • Chimeric T cells (CAR-T) (嵌合 T 細胞 （CAR-T）)

  • Cancer vaccines (limited examples yet) (癌症疫苗（目前示例有限）)

  • Checkpoint inhibitors (PD-1/CTLA-4 inhibitors) (檢查點抑製劑（PD-1/CTLA-4 抑製劑）)

• Awareness of opportunities, complexity, and challenges within immuno-oncology. (瞭解免疫腫瘤學中的機遇、複雜性和挑戰。)

Overview: Therapeutics & Immunology

• Themes: (主題：)

1. Principles of immunology (免疫學原理)

2. Allergy and hypersensitivity (過敏和超敏反應)

3. Autoimmunity (自身)

4. Therapeutics that activate the immune system (啟動免疫系統的療法)

5. Transplantation and immunosuppression (移植和免疫抑制)

6. Cancer Immunotherapy (癌症免疫療法)

5 Core Concepts

• Innate (先天)

• Adaptive (適應的)

• Antigen Specificity (抗原特異性)

• Lymphocytes (淋巴細胞)

• Effector Mechanisms (效應器機制)

• Focus: Interventions (重點： 干預)

  • Infection (Immune Activation): Vaccines, Immune stimulators (感染（免疫啟動）：疫苗、免疫刺激劑)

  • Hypersensitivity: Antihistamines, Glucocorticoids + Symptom management (超敏反應：抗組胺葯、糖皮質激素 + 癥狀管理)

  • Transplantation: Glucocorticoids, Antiproliferatives, Calcineurin inhibitors, Other immunosuppressants (移植：糖皮質激素、抗增殖藥、鈣調磷酸酶抑製劑、其他免疫抑製劑)

  • Autoimmunity: Analgesics, Glucocorticoids, Antiproliferatives, Calcineurin inhibitors, Other immunosuppressants + Symptom management (自身免疫：鎮痛藥、糖皮質激素、抗增殖藥、鈣調磷酸酶抑製劑、其他免疫抑製劑 + 癥狀管理)

  • Cancer: Checkpoint inhibitors, Cancer vaccines, T cell immunotherapy (癌症：檢查點抑製劑、癌症疫苗、T 細胞免疫療法)

Summary Themes 1-5

• Trade-off between the seriousness of the condition and the severity of the intervention. (在病情的嚴重性和干預的嚴重程度之間進行權衡。)

• More serious autoimmune conditions justify more severe immunosuppression. (更嚴重的自身免疫性疾病證明更嚴重的免疫抑制是合理的。)

• Cancer is the next frontier for immunopharmacology. (癌症是免疫藥理學的下一個前沿領域。)

How do we treat cancer?

• Surgery - excision (手術 - 切除)

• Radiation (輻射)

• Cytotoxic drugs (細胞毒性藥物)

Cancer Immunotherapy: Approaches

• Different types of phenotypes for tumors are linked to possible therapeutics. (不同類型的腫瘤表型與可能的治療方法有關。)

• Some Key Types: (一些金鑰類型：)

  • mAbs against specific Ag (針對特定抗原的 mAb)

  • Checkpoint blockade (mAbs) (檢查點阻斷 （mAb）)

  • Cancer Vaccine (癌症疫苗)

  • Transferred T cells (e.g., CAR-T) (轉移的 T 細胞（例如 CAR-T）)

  • Cytokines (細胞因數)

  • Oncolytic viruses (溶瘤病毒)

Cancer Immunotherapy: Three Conceptual Approaches

• Antigen-specific approach (抗原特異性方法)

  • Cancer vaccines (癌症疫苗)

  • Attempt to deliberately cause ‘autoimmune’ disease? (試圖故意引起「自身免疫」疾病？)

  • “CAR-T cell therapy” (“CAR-T 細胞療法”)

  • mAbs against specific tumor Ag (針對特定腫瘤 Ag 的 mAb)

• Exploit natural “immune defense” against cancer (利用天然的“免疫防禦”對抗癌症)

  • “Checkpoint inhibitors” (“檢查點抑製劑”)

  • Also cytokines (還有細胞因數)

• Preferential infection and killing of tumor cells (優先感染和殺傷腫瘤細胞)

  • Oncolytic viruses (溶瘤病毒)

Antigen-specific Approach

• Attempt to deliberately cause autoimmunity against tumor. (試圖故意引起針對腫瘤的自身免疫。)

• Need to prime an adaptive immune response to tumor. (需要引發對腫瘤的適應性免疫反應。)

• Cancer Vaccine (癌症疫苗)

  • Pro: Simple (優點：簡單)

  • Con: New technology, not well established yet (缺點：新技術，尚未建立)

• T cell immunotherapy (T 細胞免疫療法)

  • Pro: Can be effective (優點：可以有效)

  • Con: Personalized, Expensive (缺點： 個性化、昂貴)

Tumour Antigens

• Tumor cells are ‘self’ but can express specific antigens detectable by the immune system. (腫瘤細胞是“自身”的，但可以表達免疫系統可檢測到的特異性抗原。)

• The immune system has different ways to control, including immune surveillance, and a number of endogenous mechanisms to inhibit cancer. (免疫系統有不同的控制方式，包括免疫監視和許多抑制癌症的內源性機制。)

• Examples of tumor antigens: (腫瘤抗原的例子：)

  • e.g., HER-2 (breast cancer), PSA/PAP (prostate) (例如，HER-2（乳腺癌）、PSA/PAP（前列腺）)

  • e.g., Some HPV antigens (cervical cancer) (例如，某些HPV抗原（宮頸癌）)

Autoantigen in Autoimmune Disease (TAA)

• Research has identified a range of autoantigens. (研究已經確定了一系列自身抗原。)

• Not just any old protein/peptide from the body. (不僅僅是來自體內的任何舊蛋白質/肽。)

• Each disease has its own specific autoantigen(s) that is characteristic for that condition - presumably the disease cause. (每種疾病都有其自身特異性的自身抗原，這些抗原是該病症的特徵 – 可能是疾病的原因。)

Tumour-associated Antigens (TSA)

• Research has identified a range of antigens (peptides and antibody targets) which seem to be found only in certain tumor cells. (研究已經確定了一系列抗原（肽和抗體靶標），這些抗原似乎只存在於某些腫瘤細胞中。)

• Not just any old protein/peptide from the body. (不僅僅是來自體內的任何舊蛋白質/肽。)

• Challenge: is it really tumor-specific? (挑戰：它真的是腫瘤特異性的嗎？)

• Each tumor may have its own specific autoantigen(s) that is characteristic for that condition or that individual: related e.g., to mutations and cellular origin of that tumor. (每個腫瘤可能有其自身特定的自身抗原，這些自身抗原是該病症或該個體的特徵：例如，與該腫瘤的突變和細胞起源有關。)

Cancer Vaccines

• Identify tumor-specific antigen. (識別腫瘤特異性抗原。)

• These can be targeted by cancer vaccines. (這些可以被癌症疫苗靶向。)

• Vaccine combines: ANTIGEN + ADJUVANT (疫苗組合：ANTIGEN + ADJUVANT)

How do Vaccines Protect?

• 100 million100 million different colors! Only 1 recognizes each particular peptide or antigen in pathogenic microbe (100 million100 million 不同的顏色！只有 1 個識別病原微生物中的每種特定肽或抗原)

• Millions of T & B cells and antibodies that recognize pathogenic microbes (數百萬個 T & B 細胞和抗體識別病原微生物)

• Remember: Lymphocyte clonal expansion (請記住：淋巴細胞克隆擴增)

• Immunization drives clonal expansion (免疫驅動克隆擴增)

New Class: RNA Vaccines

Vaccine Types

• Live attenuated: Whole virus or bacteria, weakened to not cause disease (MMR, Rotarix, Nasal Flu vaccine, Zostavax) (減毒活疫苗：減毒整個病毒或細菌，減毒后不會引起疾病（MMR、Rotarix、鼻流感疫苗、Zostavax）)

• Inactivated: Whole virus or bacteria that has been ‘killed’ (Polio vaccine (part of the 6-in-1 vaccine)) (滅活：已被「殺死」的整個病毒或細菌（脊髓灰質炎疫苗（6 合 1 疫苗的一部分））)

• Subunit: Part of a virus or bacterium, e.g., protein (recombinant protein) (Gardasil 9 (recombinant protein and VLP), Influenza VLP) (亞基：病毒或細菌的一部分，例如蛋白質（重組蛋白）（Gardasil 9（重組蛋白和 VLP）、流感 VLP）)

• VLP: Virus-like particle (HepB (see also Gardasil9)) (VLP：病毒樣顆粒（HepB（另見 Gardasil9））)

• OMV: Outer membrane vesicle (MenB) (OMV： 外膜囊泡 （MenB）)

• Polysaccharide-conjugate: Polysaccharide with ‘carrier’ (HiB, MenC, MenACWY (polysacch. joined to tetanus toxoid)) (多糖偶聯物：帶有“載體”的多糖（HiB、MenC、MenACWY（與破傷風類毒素相連的多糖））)

• Toxoid: Inactive toxins (toxoid vaccine) (Diptheria/Tetanus/Pertussis (toxoid – all in 6-in-1)) (類毒素：非活性毒素（類毒素疫苗）（白喉/破傷風/百日咳（類毒素 - 全部合 6 合 1））)

• Viral Vector: Virus that doesn’t cause disease to deliver pathogen gene (Oxford-Astra-Zeneca COVID-19 vaccine (ChAdOx1 vector)) (病毒載體：不會導致疾病傳遞病原體基因的病毒（牛津-阿斯利康 COVID-19 疫苗（ChAdOx1 載體））)

• DNA-based: DNA encoding antigen (None in UK (ZyCoV-D in India)) (基於 DNA：編碼抗原的 DNA（英國無（印度的 ZyCoV-D））)

• RNA-based: mRNA in lipid envelope (Pfizer-BioNTech and Moderna COVID-19 vaccine) (基於 RNA：脂質包膜中的 mRNA（Pfizer-BioNTech 和 Moderna COVID-19 疫苗）)

• Newer technologies + whole cell and protein/peptide + dendritic cell vaccines (新技術 + 全細胞和蛋白質/肽 + 樹突狀細胞疫苗)

Cancer Vaccines 2

• Identify tumor-specific antigen (識別腫瘤特異性抗原)

• These can be targeted by cancer vaccines (???) (這些疫苗可以被癌症疫苗 （???） 靶向)

• PROBLEMS: (問題：)

  • Human adjuvants are not very effective (人類佐劑不是很有效)

  • Tumors seem to ‘resist’ adaptive immune response (腫瘤似乎“抵抗”適應性免疫反應)

  • May need different vaccine for each patient (每位患者可能需要不同的疫苗)

• What about peptide antigens and T cell responses? (肽抗原和 T 細胞反應呢？)

• Mostly in development/trial (e.g., BNT116 non-small cell lung cancer) (主要在開發/試驗中（例如，BNT116 非小細胞肺癌）)

• Some examples have been introduced in clinical settings e.g., Provenge – uses dendritic cells present (antigen) for metastatic prostate cancer [ATMP] (在臨床環境中引入了一些示例，例如 Provenge – 使用存在的樹突狀細胞（抗原）治療轉移性前列腺癌 [ATMP])

• Prophylaxis: Gardasil9, HepB vaccines (預防：九價HPV 疫苗（Gardasil9）、乙肝疫苗)

Recent Developments in Expanding Tumor-specific T cells

• Immunisation (免疫)

• Culture conditions drives clonal expansion (e.g., IL-2) (培養條件驅動克隆擴增（例如 IL-2）)

Recent Developments in T Cell Immunotherapy: CAR-T – Chimeric Antigen Receptor T-cells

• Kymriah (基姆里亞)

• Use: Refractory B cell acute lymphoblastic leukemia (用途：難治性 B 細胞急性淋巴細胞白血病)

• Immunization drives clonal expansion (免疫驅動克隆擴增)

• CULTURE + GENE THERAPY drives clonal expansion (培養 + 基因治療驅動克隆擴增)

• USE artificial T cell receptor in patients own cells (在患者自身細胞中使用人工 T 細胞受體)

• Example: Kymriah – Tisagenlecleucel [ATMP] (示例： Kymriah – Tisagenlecleucel [ATMP])

Monoclonal Abs vs Antigens

• AIMS: (目標：)

  • Deliver ‘toxin’ to tumor or elicit an immune response (將「毒素」輸送到腫瘤或引發免疫反應)

  • Many clinical examples with different targets, indications, mechanisms (具有不同靶點、適應症、機制的許多臨床實例)

  • Some examples (including checkpoint inhibitors – see later): (一些例子（包括檢查點抑製劑 – 見下文）：)

    • mAb: Ipilimumab (單抗：Ipilimumab)

      • Cancer: Melanoma, colorectal, non-small cell lung, renal cell carcinoma… (癌症：黑色素瘤、結直腸癌、非小細胞肺癌、腎細胞癌……)

      • Target: CTLA-4 (靶標：CTLA-4)

    • mAb: Pembrolizumab (單抗：帕博利珠單抗)

      • Cancer: Wide range cancers e.g., melanoma, cervical, gastric… (癌症：多種癌症，例如黑色素瘤、宮頸癌、胃癌、黑色素瘤、宮頸癌、宮頸癌、黑色素瘤、黑色)

      • Target: PD-1 (目標：PD-1)

    • mAb: Rituximab (mAb：利妥昔單抗)

      • Cancer: Non-Hodgkin’s Lymphoma and CLL (癌症：非霍奇金淋巴瘤和 CLL)

      • Target: CD20 (靶點：CD20)

    • mAb: Trastuzumab (單抗：曲妥珠單抗)

      • Cancer: Breast and gastric (癌症：乳腺癌和胃癌)

      • Target: HER2 (靶點：HER2)

T Cell Priming Tumour Cells: Recap

• Immune response against ‘self’ is tightly regulated to block immunopathology (e.g., tolerance, inhibitory checkpoint proteins, e.g., CTLA-4, PD-1) (針對「自身」的免疫反應受到嚴格調節以阻斷免疫病理學（例如，耐受性、抑制性檢查點蛋白，例如 CTLA-4、PD-1）)

• Recall T-cells can be activated by recognition presented tumor antigens (回憶 T 細胞可以通過識別呈遞的腫瘤抗原來啟動)

• Cancer can exploit checkpoints to evade immune response (e.g., upregulate PD-L1 – binds PD-1 on T-cell and inhibits activation) (癌症可以利用檢查點來逃避免疫反應（例如，上調 PD-L1 – 在 T 細胞上結合 PD-1 並抑制啟動）)

Checkpoint Inhibitors

• Can exploit existing immune response to tumors which are ‘switched off’ (可以利用對「關閉」的腫瘤的現有免疫反應)

• Evidence tumors can be attacked by various immune effector mechanisms (證據 腫瘤可受到各種免疫效應機制的攻擊)

• SOLUTION: REMOVE the brakes “CHECKPOINT INHIBITORS” (解決方案：移除制動器“檢查點抑製劑”)

  • Pro: Seems to work… (優點：似乎有效……)

  • Con: …BUT Only works for some people, but very harmful for others! (缺點： …但只對某些人有效，但對另一些人非常有害！)

• Checkpoint inhibitors currently becoming mainstream treatment, with expanding list of cancers (檢查點抑製劑目前成為主流治療方法，癌症種類不斷擴大)

Nobel Prize for Medicine 2018

• Allison and Honjo discoveries of inhibition of negative immune regulation: inhibition of CTLA-4 and PD-1 (Allison 和 Honjo 發現抑制負性免疫調節：抑制 CTLA-4 和 PD-1)

• Main targets: (主要目標：)

  • CTLA-4: Ipilimumab (Yervoy) (CTLA-4：伊匹木單抗 （Yervoy）)

  • PD-L1: Atezolizumab (PD-L1：阿替利珠單抗)

  • PD-1: nivolumab (Opdivo), pembrolizumab (Keytruda) (PD-1：納武利尤單抗 （Opdivo）、帕博利珠單抗 （Keytruda）)

Use of Cytokines

• A range of cytokines is used for cancer immunotherapy, mimicking endogenous mechanisms. (一系列細胞因數用於癌症免疫治療，類比內源性機制。)

• Examples include IFNs (a,b,g) – not used much, IL2 (範例包括 IFN （a、b、g） – 使用不多、IL2)

• Aldesleukin (IL-2) – renal cell carcinoma (阿地白介素 （IL-2） – 腎細胞癌)

Oncolytic Viruses

• Virus infects and preferentially kills tumor cells. (病毒感染並優先殺死腫瘤細胞。)

• Example Imlygic – modified HSV to target melanoma [ATMP] (示例 Imlygic – 針對黑色素瘤的改良 HSV [ATMP])

• Not yet many clinical examples but lots of ongoing research and examples in trials. (目前還沒有很多臨床例子，但有很多正在進行的研究和試驗中的例子。)

• Can be engineered to deliver a variety of ‘other’ proteins/mechanisms. (可以設計以提供各種「其他」蛋白質/機制。)

Current Cancer Immunotherapy

• Trade-off between autoimmunity and immunopathology vs tumor reduction (自身免疫和免疫病理學與腫瘤複位之間的權衡)

• Unclear immunology within tumors (腫瘤內免疫學不明確)

• Diverse tumor types (多種腫瘤類型)

• Genetic variation within tumors and between individuals (腫瘤內和個體之間的遺傳變異)

Summary Theme 6

• Antigen-specific priming (抗原特異性引發)

  • Cancer vaccines prime adaptive immunity against tumor (癌症疫苗對腫瘤的主要適應性免疫)

• Antigen-specific effector functions (抗原特異性效應器功能)

  • CAR-T 汽車 (CAR-T 汽車)

• REMOVE INHIBITION “Checkpoint inhibitor” (REMOVE INHIBITION “檢查點抑製劑”)

  • PD-1 inhibitor (PD-1 抑製劑)

  • CTLA-4 blockade (CTLA-4 阻斷)

• Artificial generation of anti -cancer T cell response (人工產生抗癌 T 細胞反應)

  • Mainly development/trials (主要開發/試用)

• Also cytokines (還有細胞因數)

• Monoclonal Abs (單克隆抗體)

Summary Themes 1-5 And others!

• Experimental gene therapy (SCID) (實驗性的基因治療 （SCID）)

• Vaccines activate pathogen-specific adaptive immune responses (疫苗啟動病原體特異性適應性免疫反應)

• Recombinant cytokines and synthetic innate stimulatory drugs activate inflammation (重組細胞因數和合成的先天刺激藥物激活炎症)

• Anti-histamines, glucocorticoids, and biopharmaceuticals block inflammatory signals (抗組胺葯、糖皮質激素和生物製藥可阻斷炎症信號)

• Three classes of immunosuppressant drugs block adaptive immune priming: calcineurin inhibitors, non-CNI, proliferation blockers, and mAbs block signals or kill lymphocytes (三類免疫抑製藥物阻斷適應性免疫啟動：鈣調磷酸酶抑製劑、非 CNI、增殖阻滯劑和 mAb 阻斷信號或殺死淋巴細胞)

• Analgesics block pain, providing insulin / thyroid hormones gives symptomatic relief from immunopathology (鎮痛藥可阻止疼痛，提供胰島素/甲狀腺激素可緩解免疫病理學的癥狀)

Core Concepts - Recap

• Innate (先天)

• Adaptive (適應的)

• Antigen Specificity (抗原特異性)

• Lymphocytes (淋巴細胞)

• Effector Mechanisms (效應器機制)

• Focus: Interventions (重點： 干預)

  • Infection (Immune Activation): Vaccines, Immune stimulators (感染（免疫啟動）：疫苗、免疫刺激劑)

  • Hypersensitivity: Antihistamines, Glucocorticoids + Symptom management (超敏反應：抗組胺葯、糖皮質激素 + 癥狀管理)

  • Transplantation: Glucocorticoids, Antiproliferatives, Calcineurin inhibitors, Other immunosuppressants (移植：糖皮質激素、抗增殖藥、鈣調磷酸酶抑製劑、其他免疫抑製劑)

  • Autoimmunity: Analgesics, Glucocorticoids, Antiproliferatives, Calcineurin inhibitors, Other immunosuppressants + Symptom management (自身免疫：鎮痛藥、糖皮質激素、抗增殖藥、鈣調磷酸酶抑製劑、其他免疫抑製劑 + 癥狀管理)

  • Cancer: Checkpoint inhibitors, Cancer vaccines, T cell immunotherapy (癌症：檢查點抑製劑、癌症疫苗、T 細胞免疫療法)

Learning Outcomes: Recap

• It may be possible to target cancer by deliberately manipulating the immune system (有可能通過故意縱免疫系統來靶向癌症)

• Know different therapeutic strategies and identify clinical examples of those that have succeeded to date, e.g.: (瞭解不同的治療策略並確定迄今為止成功的臨床範例，例如：)

  • Chimeric T cells (CAR-T) (嵌合 T 細胞 （CAR-T）)

  • Cancer vaccines (limited examples … yet) (癌症疫苗（有限的例子……還沒有）)

  • Checkpoint inhibitors (PD-1/CTLA-4 inhibitors) (檢查點抑製劑（PD-1/CTLA-4 抑製劑