Tumor Immunity

Question 1

What are the general features of tumor immunity (3)?

Answer 1

1. Tumors stimulate specific, adaptive immune responses
2. Immune responses frequently fail to prevent tumor growth
   
   • Immune system is designed to prevent ‘self’ reactivity, so mechanisms are in place to prevent immune reactivity to cancerous cells
3. Immune system can be “activated” by external stimuli to kill tumor cells and eliminate tumors

Question 2

What is immune surveillance? What are the problems with this particular proposal?

Answer 2

• Immune surveillance: immune system prevents the outgrowth of “transformed” cells
• Drawbacks:
  
  • cancers arise in immune competent individuals
  • cancer formation is a step-wise process

Question 3

What observations led to the proposal of immune surveillance? What conclusions were made from these observations?

Answer 3

1. Histopathological and clinical:
   
   • ​​lymphocyitc inflitrates around some tumors and enlargement of lymph nodes correlates with better prognosis ⇒ immune responses against tumors inhibit tumor growth
2. Experimental:
   
   • ​​transplant of tumor is rejected in animals, and even more quickly if the animal has already been exposed; immunity to tumor transplants can be transferred by lymphocytes from a tumor bearing animal ⇒ tumor rejection shows features of adaptive immunity and is mediated by lymphocytes
3. Clinical and Experimental:
   
   • Immunodeficient individuals have an increased incidence of some types of tumors ⇒ immune system protects against the growth of tumors

Question 4

What is immunogenicity?

Answer 4

Immune system controls not only tumor quantity but also tumor quality

Question 5

Which Immune Cells are Involved in Cancer Immunity?

Answer 5

• Innate Immunity: (present at all times; does not increase with repeated exposure; no antigen specificity)
  
  1. NK cells
  2. Granulocytes
  3. Macrophages
  4. gamma/delta T cells
  5. Dendritic cells
• Adaptive Immunity: (requires induction)
  
  1. B cells
  2. T cells

Question 6

What are the most important cells in tumor immunity?

Answer 6

• the most important cells appear to be T cells and antigen-presenting cells (APC)
  
  • including dendritic cells
    
    • best “professional” APC

Question 7

How Does the Immune System Recognize the Tumor Cells as “Foreign”?

Answer 7

Tumor Antigen Recognition

• Cancer cells will often express MHC class I proteins, but frequently fail to express MHC class II
• CD8 T cells can recognize tumor antigens on the cancer cells that have been processed endogenously and presented in the context of MHC class I
• Tumor cells usually lack important second signals (co-stimulatory molecules)
• CD8 cells require professional antigen-presenting cells (APC) to become activated (“cross-presentation”)
• CD4 T cells are also important for effective cancer immunity ⇒ also avtiavted by APC

Question 8

Describe the difference between the exogenous and endogenous pathways for tumor antigen recognition:

Answer 8

1. Exogenous Pathway: [class II]
   
   • Antigen-presenting cells (APC) capture tumor proteins (shed or from dying cells) from the microenvironment
   • process the proteins
   • present the peptide antigens (processed peptides)
2. Endogenous Pathway: [class I]
   
   • Tumor cells themselves can process cytoplasmic proteins into peptides (antigens) that get presented by MHC class I
   • Alternatively, tumor proteins taken up by APC get processed by the MHC class I pathway

Question 9

Why are APCs, such as dendritic cells so important for tumor antigen recognition?

Answer 9

Professional APC (Dendritic Cells) Important for:

1. presentation of tumor antigens to T cells
2. providing important second signals to the T cells (via co-stimulatory ligands) so that the T cells become activated

Question 10

Describe how APCs activate reactive T cells to fight against tumors:

Answer 10

1. Tumor antigens are cross-presented to CD4 and CD8 T cells by professional APC
2. Co-stimulatory proteins on the APC provide important second signals to the T cells (both CD4 and CD8)
3. The activated CD4 T cells provide “help” to the CD8 T cells in the form of cytokines and increased APC co-stimulation
   
   • increase co-stimulatory protein expression on APC by binding CD40
4. Once CD8 T cells are activated ⇒ mediate effector functions ⇒ cytolytic T lymphocytes (CTLs)
5. Activated CD8 CTL can now directly see MHC I peptide (tumor antigen) on tumor cells and NO LONGER require the presence of co-stimulatory proteins

Question 11

Barriers to Cancer Immunity:

Answer 11

1. IDO (indoleamine 2,3 dioxygenase) **overexpression **
2. Expansion and recruitment of regulatory cells
3. Secretion of immunosuppressive cytokines and soluble factors
4. Activation of negative regulatory pathways
5. Evasion of immune recognition

• ​​​Can directly inhibit T cells or suppress T cell reactivity by negatively affecting antigen presenting cells

Question 12

What is the current approach to breaking immune tolerance to cancer?

Answer 12

Answer: Immunotherapy

• Need to interfere with suppression and/or bypass the suppression by “over-stimulating” immunity

Question 13

List the 3 approaches to cancer immunotherapy:

Answer 13

1. Monoclonal Antibodies
2. Adoptive Cellular Immunotherapy
   
   1. T cells – TILs, genetically engineered, allogeneic)
3. Vaccines (T and B cells)

Question 14

What are potential targets for monoclonal antibody therapy of cancer?

Answer 14

1. tumor-associated blood vessels
2. vascular growth factors (for example, VEGF) or their receptors
   
   • for example VEGFr or Her2/Neu (epidermal growth factor receptor 2)
3. diffuse malignant cells (for example, leukemia),
4. tumor cells within a solid tumor
5. tumor associated stroma
   
   • for example, fibroblasts or myeloid cells

Question 15

How are monoclonal antibodies used to interfere with immune suppresion?

Answer 15

Block “immune checkpoints”

Question 16

Monoclonal Antibodies:

Mechanisms of Action

Answer 16

1. Unconjugated antibody (example - Rituximab)
   
   • Must rely on:
     
     1. complement
     2. antibody-dependent cellular cytotoxicity (ADCC)
     3. direct clearance by other Fc receptor (FcR)-bearing cells
     4. ability to block interactions between receptors and ligands involved in cancer progression
2. Antibody conjugates
   
   • Carry a payload:
     
     1. Plant (Ricin), bacterial
        
        • diptheria or pseudomonas toxin
     2. fungal toxins
        
        1. inhibitors of protein synthesis
     3. radio-isotopes
3. T cell binding epitopes
   
   • ​​“bi-specific” antibody
     
     • anti-CD3 + anti-tumor antibody

Question 17

Monclonal Antibody therapy:

CTLA4 Blocking Antibodies

Answer 17

• CTLA4 was the first immune checkpoint targeted in an effort to treat cancer
• Two anti-CTLA4 antibodies have been tested in advanced clinical trials
  
  • ipilimumab
    
    • FDA-approved for the treatment of advanced melanoma
  • tremelimumab
• One of the major toxicities of anti-CTLA4 therapy: triggering of autoimmunity against the gut, the skin, the liver, and endocrine system
  
  • ​occur in about 60% of patients
  • sometimes is lethal

Question 18

Monoclonal Antibody Therapy:

PD-1 Blocking Antibodies

Answer 18

• In early phase clinical trials, approximately 20% to 30% of patients with advanced, treatment:
  
  • refractory melanoma, non–small-cell lung cancer, or kidney cancer have experienced objective tumor regressions
  • Fewer toxicities than anti-CTLA4
• One clinical trial has been conducted to date, where anti-PD-1 and anti-CTLA4 were combined
  
  • Acceptable toxicity profile
  • Results appear to be better than treatment with either alone

Question 19

Monoclonal Antibodies:

Potential Limitations

Answer 19

• Mutation or down-modulation of tumor antigens
• Typically derived from mice or rats so they induce potent rejection responses in humans
  
  • To avoid this problem, antibodies can be genetically “humanized”

Question 20

What has been the “only effective” experimental therapy of patients with advanced metastatic melanoma?

Answer 20

Adoptive T Cell Immunotherapy

Question 21

Describe how TILs are used in adoptive T cell immunotherapy:

Answer 21

• Lymphocytes can be cultured from tumors removed by surgery
  
  • These are referred to as tumor-infiltrating lymphocytes (TILs)
• TILs can be expanded in culture ⇒ given back to patients to provide large numbers of highly activated T cells that recognize the cancer cells
  
  • A way of bypassing the tumor suppressive mechanisms

Question 22

What is a potential drawback to using adoptive T cell immunotherapy? Give an example.

Answer 22

Immune system can target non-mutated self-antigens overexpressed on cancer cells:

• Example: Melanoma patients
  
  • patients that have responded to TIL therapy usually develop non-life threatening vitiligo (loss of skin pigmentation)
    
    • sometimes uveitis
  • due to melanocyte reactivity

Question 23

Chimeric antigen receptors (CARs) are used in what type of immunotherapy?

Answer 23

Adoptive cellular immunotherapy with genetically engineered T cells

Question 24

CAR T cells:

• Benefits:
• Risks:

Answer 24

• Benefits:
  
  • Can persist for years
  • CAR-modified T cells still express their native antigen receptors
  • All of the modified T cells are now able to recognize the same antigen
  • Become very strongly activated when the antibody portion of the receptor binds to its antigen
• Risks:
  
  1. T cells are so strongly activated that they can make large amounts of pro-inflammatory cytokines
     
     • result in a “toxic shock-like” syndrome
  2. If the tumor antigen is also expressed on normal tissues ⇒ could be autoimmune toxicity
  3. Tumor antigen may be lost
  4. Does not work well for treating solid tumors

Question 25

Explain how allogeneic T cells (hematopoietic stem cell transplantation) are effective in cancer immunotherapy

Answer 25

• Donor T cells that are transferred to the host (patient) along with the hematopoietic stem cell graft become activated to host alloantigens
• These activated donor T cells can attack host tissues and cause graft-versus-host disease (GVHD)
• They can also eliminate residual host cancer cells that express the alloantigens

Question 26

Describe the graft-versus-tumor effect:

1. Indirect
2. Direct

Answer 26

Indirect

• Withdrawal of immune suppression, or a flare of graft-versus-host disease (GVHD) induces complete remissions in some patients with relapsed leukemia
• Autologous HSCT has a higher risk for tumor relapse than allogeneic HSCT
• GVHD after HSCT is associated with a lower risk of tumor relapse
• Depletion of T cells from the donor graft results in an increased risk of tumor relapse

Direct

• Infusions of donor lymphocytes (T cells) to a patient when they relapse after allogeneic HSCT can re-establish complete tumor remissions

Question 27

Cancer vaccines may be useful because they activate what?

Answer 27

may activate both T and B cells