Cancer Immunotherapy

What is the cell based immune response against tumors?

• Immune system activated by antigens presented on surface of cancer cells

• DC are professional antigen presenting cells and when they see cancer cells with antigens presented on the surface, they take up the tumor antigens

• DC enter lymphatic tissues (lymph nodes) and mature → mature DCs present antigens to T-cells

• Activated T cells (by the antigens from DCs) leave lymph nodes and migrate to the tumor (cancer) to bear antigens and destroy tumor cells

What is the mechanism by how tumors acquire immune tolerance?

• While this process of recognition and activation of T cells is going on, the cancer can provide its own defenses

• Cancers have good ability to evade immune response due to combo of different factors

• Cancer can overtime withstand immune response → tumors acquire immune tolerance and the 1st step is called immune editing

• Tumorigenesis (formation of tumor) → there are highly immunogenicity tumor cells (high conc of antigens on their surface), we also have poorly immunogenicity tumor cells (won’t present same degree of antigens) so there’s heterogenicity of cells → as tumor grows, the immune system recognize the highly immunogenicity tumor cells (T cells destroy the highly immunogenicity tumor cells) leaving just the poorly ones

  • You only have cancer predominantly of poorly immunogenicity cells where tolerance develops

• This process: immune editing → where body removes highly antigenic tumor cells for the poorly immunogenicity ones to remain

How do poorly immunogenic cells contribute to immune tolerance?

• Poorly immunogenicity tumor cells contribute to process of immune tolerance by creating environment that is immunosuppressive (release cytokines, molecules (TGF-beta, IL10) that attract T-reg cells, and stromal cells that form a barrier)

  • It also downregulates genes encoding for proteins invovled in antigen presentation on tumor cells

What are tumor-specific antigens and examples?

• Tumor specific antigen → perfect scenario where antigens present in tumor cells but absent in normal cells (specificity of immune response is concentrated to tumor cells)

  • Present in cancer cells from oncogenic viral proteins or mutation

  • Ex: HPV associated cancer of cervix, KRAS (oncogene) mutations in different cancers (pancreatic/lung)

What are tumor-associated antigens and examples?

• Tumor associated antigen → antigens predominantly present on cancels cells, there might be low expression in normal cells but much higher in cancer cells

  • Low expression on normal cells; disproportionately expressed on tumor cells

  • Ex: EGFR and HER-2 over-expressing cancers, prostate cancers overexpressing PAP

    • Ex: Trastuzumab attacks HER-2 on cardiac cells too to give toxicity

What are the different cancer immunotherapy classifications?

• Immune checkpoint inhibitors

• MAB against cell surface markers

• Cell based immunotherapy (Adoptive Cell Transfer)

• Cytokines

Explain why CTLA-4 is the 1st immune checkpoint that we wanna inhibit?

• Immune checkpoint: regulatory step by which immune system and immune response is regulated

  • 2 immune checkpoints

  • 1st in lymph nodes called CTLA4 which is an immune checkpoint that prevents excessive stimulation of effector T-cells

    • It regulates interaction between APCs and T cells

    • APCs display the antigen on the MHC → 1st signal called priming signal is initiated when T cell receptor binds to the antigen that is bound to MHC so T cells are being primed

    • 2nd signal is the activating signal where you have binding of B7 (receptor on surface of DCs/APCs binding to CD28 on T cells) so now T cells are activated

    • The T cells now migrate out of lymph nodes and go where antigens on surface of cancer is expressed and destroy the cancer cells

    • We have an inhibitory signal from CTLA4, present on the inside of T cells and when it migrates to surface of T cells, it interacts with B7 causing CD28 to dissociate from B7

      • BASICALLY, the inhibitory signal eliminates the activating signal (of the B7 interaction with CD28) b/c CTLA4 has higher binding affinity towards B7 vs CD28 → T cells being inactivated

  • CTLA-4 Is a co-inhibitory receptor on T cells

  • So if we wanna stimulate the T cells, we wanna inhibit CTLA-4 to maximize the activation of T cells since no inhibitory signal turned on which is why CTLA4 is a checkpoint we wanna inhibit

What is known about CD28:B7 binding vs CTLA:B7 binding?

• With weak TCR signal, CD28:B7 binding predominates and a net positive activating signal, IL-2 production, cell proliferation + survival of T cells

  • IL2 causes the survival of T cells

• With a strong TCR signal, CTLA:B7 binding predominates so net negative signal, reduced IL-2 production, reduced proliferation and survival of T cells

• KEY POINT: CTLA-4 limits T-cell responses early in an immune response, primarily in lymphoid tissues

What is Ipilumumab and the indication?

• Ipilimumab → CTLA-4 antibody

  • Binding to CTLA-4 results in its neutralization and subsequent inhibition of T cell inactivation (NO B7 BINDING and preserves CD28:B7 interaction)

  • T cells continue to proliferate and more cancer destruction

• Indication: tx of melonoma → b/c melanoma cancers display tumor associated antigens (MAGE) expressed in melanoma tissue and absent in normal tissues

  • Enhanced survival in pts with advanced melanoma

What is the AEs of Ipilimumab? Can response be predicted from biomarkers?

• Immune related AE in the skin + GI due to immune enhancements

• Response to Ipilimumab can NOT be predicted based on objective biomarker level

What is the second immune checkpoint happening between? (PD-1)

• Happening between T cell and cancer/tumor cell

• Reminder: between APC and T cell we had the 1st checkpoint CTLA-4

Explain PD-1?

• Programmed death-1 is expressed on T cells and bind to programmed death ligands (PDL-1 or PDL-2)

  • Signals death/inhibition of T cells

  • When PD-1 activates, T cells get inhibited

  • Certain types of cancers can overexposes PD-1, cancer cell can then resist effect of T cells (mechanism of resistance of cancer cells)

• PD-1 pathway regulates previously activated T cells at the later stages of an immune response, primarily in peripheral tissues

• PD-1/PD-1/2 is a co-inhibitory signal that results in inhibition of T cell activation, proliferation and reduces T-cell survival

• PD1 ligands can be INDUCIBLY expressed by non immune cells, including tumor cells

What are some mechanisms of immune system evasion by tumors?

• A → ineffective presentation of tumor antigens to the immune system

  • Downregulate MHC expression and suppress APC

• B → Recruitment of immunosuppressive cells

• C → release of immunosuppressive factors

• D → T cell checkpoint dysregulation

Prolonged T cell receptor stimulation can cause what? Release of of cytokines by T cells up regulates what?

• Prolonged TCR stimulation during immune response can cause unregulated PD-1 expression of T cells

• Release of pro inflammatory cytokines by T cells up regulates PD-L1 expression by tumor cells or via ontogenetic mutations

• PD-1/PD-L1 binding results in reduced T-cell proliferation, reduced proinflamamtory cytokine production and reduced survival

What are the PD-1 inhibitors and PD-L 1 inhibitors?

• PD-1 Inhibitors:

  • Nivolumab (Opdivo)

  • Pembrolizumab (Keytruda)

• PD-L1 Inhibitors:

  • Durvalumab (Imfinzi)

• Tumor PD-L1 expression can be used as a predictive marker for response to the use of PD-1 and PD-L1 inhibitors.

• PD-L1 is used as a marker to determine patient eligibility to receive these treatments

  • B/c these are over expressed by cancers, can be used as markers

What is prevalence of IRAE’s following tx?

• Immune related adverse effects:

  • CTLA-4

  • PD-1

  • PDL-1

• Consistent trend is that CTLA-4 has higher prevalence of IRAEs b/c it happens early on in lymph nodes, stimulate immune response against any kind of antigen being presented by tissues b/c it is nonspecific (antigens presented by cancers is NOT the only antigens in the lymph tissues)

  • Early stage of immune response and nonspecific response of CTLA-4 causes more IRAE

• PD-1 and PDL-1 is in peripheral tissues SO majority is between T cell and cancer cells → LOWER degree of IRAEs

What is the newest tx (combination of CTLA-4 and PD-1/PDL-1)?

• You wanna try to inhibit BOTH checkpoints early on

• CTLA-4 blockade allows more activation of T cells in lymph nodes and inhibits T-reg function

• PD-1 pathway blockade restores activity of anti-tumor T cells at tumor site

• (Issue is cumulartive IRAEs → a lot more b/c you ramp up immune response)

What are the MABs against cancer cell surface markers?

• Rituximab → chimeric that is the R in R-CHOP for B cell non-hodgkin lymphoma

  • Against CD20

  • CD20 is cell surface marker on mature B cells and cancerous B cells

• We also have Ofatumumab (Human) against CD20

• Binding to CD20 causes

  • Apoptosis

  • ADCC

  • Complement dependent cytotoxicity

What is a way to combine immunotherapy and radiotherapy?

• 90Y-Ibritumomab:

  • Ibritumomab → mouse MAB against CD20

  • Linker is Tiuxetan → linker chelator covalently attached to mab and has high affinity chelating site for 90Y

• 90Y: pure Beta radiation/particle emitter with half life 64 hrs, beta rays can penetrate soft tissues up to 4 mm

  • B radiation is class of ionizing radiation that damages DNA resulting in DNA strand breaks

What are adoptive cell transfer: engineered T cells?

• Isolate T cells and engineer them to identify epitome/marker on cancer and re-infuse them again (highly individualized tx → expensive and reserved if other tx don’t work)

• CAR-T (chimeric antigen receptor) T cells!

  • Re-engineer pts own T cells to recognize specific cancer antigen

• Med: Tisagelecleucel → KYMRIAH which is cell based therapy for diffuse large B cell lymphoma

  • Lymphoma cells have CD19 on surface → insert the chimeric receptor INSIDE T cell

    • Extracellular domain → antigen recognition (binds the CD-19)

    • Intracellular domain → once antigen binds to extracellular part, 2 signals by intracellular domain results in T cell activation and cancer cell destruction

What are the nonspecific immune stimulants (IL2)?

• Aldesleukin (Proleukin)

  • Recombinant human interleukin-2 (IL-2)

  • Endogenously produced by NK and T-cells (T helper cells)

  • Major physiologic role: Promote activation and proliferation of T and NK cells in autocrine and paracrine manner.

    • Promote cytotoxic T cells

• Toxicity:

  • Capillary leak syndrome

    • Increase in leakiness of small blood vessels

    • Characterized by hypotension, tachycardia, swelling of arms, legs, pulmonary edema

What are the interferons, S/E?

• Type 1: IFNa, IFNb

• Type 2: IFN gamma

• IFNs activate dendritic cells, NK cells, cytoxic T cells + suppress function of MDSC

• S/E: flu sx, fatigue, neuropsychiatric