cancer immunology

What is the balance that characterizes cancer?

A usually highly regulated balance between cell renewal and cell death, leading to net cell growth.

What external factors influence cellular growth control?

Instructions from outside the cell, such as growth factors, which function via cell surface receptors.

What are the two types of oncogenes?

v-onc (viral oncogenes) and c-onc (cellular oncogenes).

What types of mutations can induce tumor formation?

Mutations that affect genes inducing cell proliferation (proto-oncogenes), inhibiting proliferation (tumor suppressor genes), and regulating programmed cell death.

What is immune surveillance in the context of cancer?

The recognition of cancers by components of the immune system, where tumor antigens can trigger immune responses that kill tumor cells.

What types of tumor antigens are recognized by T cells?

Tumor-exclusive antigens, mutated normal antigens, antigens expressed at the wrong stage of cell growth, and overexpressed antigens.

Why is T cell recognition of tumor antigens normal in hematopoietic cancers?

Cancerous blood cells come into contact with naïve T cells, and some hematopoietic cells express high levels of B7.

What challenges do T cells face in recognizing tumors in solid organs?

Naïve T cells typically do not move into tissues, tumor cells may lack co-receptors to activate T cells, and mutations can prevent recognition.

How can viruses contribute to cancer development?

Viruses that establish long-term infections can evade the immune system and potentially lead to cancer.

What role do Tregs play in cancer?

Inducible or adaptive Tregs expand and suppress anti-tumor immune responses, aiding tumor escape.

How do macrophages recognize tumors?

By identifying unusual cell surface molecules, such as phosphatidylserine, and producing TNF-alpha to cause tumor necrosis.

What triggers NK cell activation against tumors?

NK cells target cells with low levels of MHC I and unusual surface proteins, often activated by tissue damage from tumors.

What is the role of antibodies in response to tumor antigens?

Tumor-specific antibodies can induce tumor cell death through complement activation and antibody-dependent cell-mediated cytotoxicity (ADCC).

What is a potential negative effect of anti-tumor antibodies?

Anti-tumor antibodies can enhance tumor growth by blocking CTL responses or preventing T cells from binding to antigens.

What happens to tumor antigens in leukemic T cells when antibodies bind?

Ab-Ag binding induces capping, endocytosis, and/or shedding, preventing leukemic cells from presenting antigens.

How can tumor cells affect MHC I expression?

Tumor cells can express less MHC I due to downregulation by viruses or as a consequence of natural selection.

What is a consequence of insufficient co-stimulation in tumors?

Most tumor cells do not produce co-stimulatory molecules, and a lack of antigen-presenting cells (APCs) reduces the likelihood of co-stimulation.

What are the two main strategies to activate the immune system against cancer?

General boost (adjuvant/cytokine) and specific activation (vaccines).

What are some immune-related 'weapons' used in specific targeting of cancer?

Monoclonal antibodies, lymphocytes (T cells, NK cells), and phagocytes (macrophages).

What is the function of monoclonal antibodies in cancer treatment?

Monoclonal antibodies efficiently recognize and bind specific epitopes, with functions varying according to their isotype.

What is Rituximab and what does it target?

Rituximab (Rituxan) targets CD20 in non-Hodgkin's lymphoma and is a chimeric IgG1 approved in 1997.

What is the mechanism of action for Trastuzumab?

Trastuzumab (Herceptin) targets HER-2, expressed in 25% of breast cancers, and is a humanized IgG1 approved in 1998.

What is Gemtuzumab ozogamicin and its target?

Gemtuzumab ozogamicin (Mylotarg) targets CD33, expressed in 80% of acute myeloid leukemia cases, and is linked to a calicheamicin derivative that induces DNA strand breaks.

What is the purpose of J591 in cancer treatment?

J591 is a human monoclonal antibody specific for prostate-specific membrane antigen, currently in trials with a radioactive isotope for targeted therapy.

What is Ipilimumab used for?

Ipilimumab (Yervoy) is a human monoclonal antibody used for melanoma treatment and in clinical trials for other cancers.

How does Nivolumab enhance T cell response?

Nivolumab blocks the negative regulator PD-L1, preventing it from binding to PD-1 on T cells, thus enhancing their response to cancer cells.

What is the significance of T cells in tumor immunity?

T cells can recognize tumor-specific antigens, leading to protective immune responses against tumors.

What types of antigens can induce an immune response without self-tolerance issues?

Antigens normally expressed only in embryos, gene products of mutated genes, cancer-testis antigens, and viral antigens.

What is the impact of HPV vaccines on cervical cancer rates?

HPV vaccines have reduced cervical cancer rates by 62% in women vaccinated between ages 14-16 and 34% in those aged 16-18.

What role do B7 transfected tumor cells play in enhancing immunity?

B7 transfected tumor cells can provide co-stimulation for CTLs, leading to tumor regression in experimental models.

What is the role of adjuvants in macrophage activation?

Adjuvants activate macrophages, making them more efficient T cell activators by increasing cytokine expression and enhancing class II MHC and B7.

Name two examples of adjuvants used to activate macrophages.

BCG (Bacillus Calmette-Guerin) and Corynebacterium parvuum.

What is a potential method for administering adjuvants?

Adjuvants can be injected into a local area or mixed with killed excised tumor cells before re-injection.

What are some cytokines evaluated in cytokine therapy?

IFN-alpha, IFN-beta, IFN-gamma, IL-2, IL-4, IL-6, IL-12, GM-CSF, and TNF.

What is a challenge associated with systemic cytokine administration?

Systemic administration can have severe side effects.

What is the effect of IL-2 in cytokine therapy?

IL-2 activates T cells and NK cells but can be toxic, necessitating local administration.

Which interferon is licensed for use and what cancers does it treat?

IFN-alpha is licensed for lymphoid cancers (e.g., hairy cell leukemia, chronic myelogenous leukemia, non-Hodgkin's lymphoma), melanoma, Kaposi's sarcoma, and renal cancer.

How does IFN-alpha enhance immune response?

It increases MHC I expression on tumor cells and MHC II expression on macrophages, enhancing CTL activity and macrophage activation.

What is the role of TNF in cancer therapy?

TNF-alpha and TNF-beta can directly kill tumor cells, cause hemorrhagic necrosis, and inhibit angiogenesis.

What are T cell transfer therapies designed to do?

They aim to remove T cells from the immunosuppressive environment, allowing for activation and clonal expansion before transferring them back into the host.

What is the purpose of genetically engineering T cells?

To enable them to recognize tumor-associated antigens and enhance anti-tumor responses.

How can patient T cells be genetically modified?

TCRs can be cloned from patient T cells and inserted into retroviruses or lentiviruses to infect autologous T cells.

What are Chimeric Antigen Receptors (CARs)?

CARs are engineered receptors that allow T cells to recognize MHC-non restricted structures on target cells.

What is the significance of humanized mice in T cell therapy research?

They can express human MHC I/II molecules and can be immunized with tumor antigens of interest.

What is the outcome of ex vivo expansion of T cell populations?

It can trigger death and complete eradication of tumors in some cases.

PD-1/PD-L1 axis

Tumor cells express PD-L1, which binds PD-1 on T cells and sends an inhibitory signal ('don't kill me'). Anti-PD-1 antibodies block this.

CTLA-4 axis

CTLA-4 competes with CD28 for B7 binding. When CTLA-4 wins, T cells don't get co-stimulation and become inactive. Anti-CTLA-4 antibodies block this.

Checkpoint blockade

These checkpoints normally prevent autoimmunity, but tumors hijack them to evade destruction.

MAGE-3 Cancer Vaccine

A vaccine targeting MAGE-3, a cancer-testis antigen expressed on melanoma and some colorectal cancers.

Phase II trial of MAGE-3 vaccine

Showed promise with CTL induction and tumor regression correlating with anti-MAGE-3 T cell numbers.

Phase III trial of MAGE-3 vaccine

Failed to show benefit over standard treatment.

Viral Vector Vaccine for Prostate Cancer

Construct includes plasmid DNA encoding PSA plus co-stimulatory molecules (LFA3, ICAM1, CD80) packaged into vaccinia or fowlpox virus.

Mechanism of Viral Vector Vaccine

Injected intradermally, virus infects epithelial cells, leading to necrosis and release of PSA for APC uptake.

Role of co-stimulatory molecules

They enhance T cell activation, making the vaccine more immunogenic than PSA alone.

B7-Transfected Tumor Cells

Transfecting tumor cells with the B7 gene allows them to express B7 on their surface.

Signal 1 in T cell activation

CTL precursor binds via TCR-MHC.

Signal 2 in T cell activation

CD28 on CTL binds B7 on tumor cell for full activation.

Clinical application of B7-transfected cells

Used in some therapeutic cancer vaccines where patient tumor cells are modified ex vivo and reinfused.

Adoptive T Cell Therapy (TIL Therapy)

Harvest T cells that have already infiltrated the patient's tumor, expand them in the lab, then reinfuse.

Steps in TIL Therapy

Obtain tumor sample, fragment to isolate TILs, activate and select T cells, expand using IL-2 and other growth factors.

Immunosuppressive microenvironment

Contains Tregs, MDSCs (myeloid-derived suppressor cells), and tumor cells.

Lymphodepleting chemotherapy

Removes competing immune cells and creates 'space' for the infused T cells.

Infusion of T cells

The process of reintroducing expanded tumor-specific T cells back into the patient.

Why lymphodepletion?

Eliminates Tregs and other suppressive cells, removes cytokine 'sinks' so IL-2 is available for infused cells, and creates homeostatic signals that promote T cell expansion.

TCR Gene Therapy

A method to give a patient's T cells a tumor-specific T cell receptor they didn't originally have.

Process of TCR Gene Therapy

1. Take tumor sample from patient 2. Isolate T cells that infiltrate the tumor 3. Test for avidity 4. Identify the best tumor-specific TCR 5. Clone the TCR genes into a viral vector 6. Transduce the patient's own T cells with this vector 7. Expand in culture 8. Infuse back into patient.

Advantage of TCR Gene Therapy

You can take any T cell and give it tumor specificity — you're not limited to the small number of TILs that naturally exist.

Limitation of TCR Gene Therapy

TCRs are MHC-restricted, so this only works for patients with matching HLA types.

CAR

Chimeric Antigen Receptor — a synthetic receptor combining antibody variable region, transmembrane domain, and intracellular signaling domains.

Construction of CAR

1. Take an antibody specific for a tumor antigen 2. Clone the variable regions 3. Attach to a genetically engineered activating motif 4. Clone into retroviral vector 5. Transduce patient's T cells 6. Infuse into patient.

Key advantage of CAR-T therapy

CARs recognise surface antigens directly — no MHC restriction, works regardless of patient's HLA type.

Clinical success of CAR-T therapy

Anti-CD19 CAR-T (Kymriah, Yescarta) is FDA-approved for B cell malignancies.

Generating TCRs Using Transgenic Mice

A method to find tumor-specific T cells by creating a transgenic mouse expressing human MHC and immunizing it with human tumor antigens.

Creative solution for TCR generation

1. Clone human MHC class I (or II) genes 2. Create a transgenic mouse expressing human MHC 3. Immunise this mouse with human tumor antigens 4. Isolate the mouse T cell with the best specificity 5. Clone its TCR into a viral vector 6. Transduce human T cells with this mouse TCR 7. Infuse into patient.

Why does TCR generation using transgenic mice work?

The mouse immune system hasn't been tolerised to human tumor antigens, allowing it to mount a strong response.

Avidity

How strongly T cells bind to tumor antigens.

Pathway A — Pro-apoptotic signal

Targeted therapy (e.g., kinase inhibitors) induces tumor cell death directly.

Pathway B — Increased antigen presentation

Dying tumor cells release antigens → APCs present tumor-derived peptides on MHC I → recruits and activates both adoptively transferred T cells AND endogenous T cells.

Pathway C — Decreased immunosuppression

Some targeted therapies reduce Tregs and MDSCs in the tumor microenvironment.

The cycle

Activated T cells proliferate → kill more tumor cells → release more antigen → activate more T cells.

Key insight

Targeted therapy can 'prime' the immune system by creating antigen release and reducing immunosuppression, making adoptive cell transfer more effective.

CAR-T

Chimeric Antigen Receptor T cells, a type of immunotherapy that modifies T cells to better attack cancer.

CAR-NK

Chimeric Antigen Receptor Natural Killer cells, an alternative to CAR-T that has a safer toxicity profile.

Cytokine release syndrome

A major risk associated with CAR-T therapy but minimal or none in CAR-NK therapy.

Neurotoxicity

Significant risk in CAR-T therapy but minimal in CAR-NK therapy.

Graft-vs-host disease

Risk in allogeneic settings for CAR-T but low risk for CAR-NK.

Manufacturing

CAR-T must be autologous (patient-specific) while CAR-NK can be 'off-the-shelf' (allogeneic).

Killing mechanisms

CAR-T is CAR-dependent, whereas CAR-NK uses multiple mechanisms (CAR + natural cytotoxicity receptors).

Immunological tolerance

The immune system has been educated NOT to attack self-antigens, leading to deletion or suppression of T cells with high affinity for these antigens.

Risk of autoimmunity

Breaking tolerance to a self-antigen may lead to attacking healthy tissues expressing that antigen.

Transgenic mice research

Using transgenic mice with varying expression levels of artificial self-antigens to understand when tolerance can be safely broken.

Key finding

Immunity against self-antigens IS possible if expression isn't too high or widespread.

Antigen: p53

Tested in clinical trials for colorectal cancer and others.

Antigen: Ep-CAM

Tested in clinical trials for colorectal cancer.

Antigen: CEA

Carcinoembryonic antigen tested in clinical trials for colorectal cancer.

Antigen: MUC-1

Tested in clinical trials for colorectal cancer.

Antigen: Tyrosinase

Tested in clinical trials for melanoma.

Encouraging result

Vaccines targeting CEA and p53 can generate specific CTLs without obvious autoimmune disease, suggesting tolerance CAN be broken safely in some cases.

What problem does Herceptin (Trastuzumab) address in breast cancer?

It targets HER2 gene amplification, which leads to excessive growth signaling in cancer cells.

How does Herceptin inhibit tumor cell growth?

By binding to the HER2 receptor and blocking EGF from binding, preventing growth signals.