Cancer Immunotherapy Notes

Cancer Immunotherapy

Interface Between Cancer and the Immune System

  • Dr. Jason Adhikaree, Clinical Associate Professor, University of Nottingham

Cancer Immunotherapy Approaches

  • Monoclonal antibodies
    • Conventional mAbs
    • Drug antibody conjugates (ADCs)
    • Redirected T cells (bispecific mAbs)
    • Checkpoint inhibitors
  • Cancer Vaccines
    • Oncolytic viruses
    • Peptide vaccines
  • Adoptive T cell transfer
    • Tumor-infiltrating lymphocytes (TILs)
    • Chimeric antigen receptor (CAR) T cells

Antibodies Can Kill Tumor Cells by Multiple Mechanisms

  • Effector Function:
    • Conventional mAbs: Target cell signaling, leading to apoptosis or growth arrest. Complement-mediated lysis and opsonization via C1. ADCC (antibody-dependent cell-mediated cytotoxicity) by macrophages or natural killer cells via FcR.
    • ADCs: Antibody-drug conjugates deliver cytotoxic drugs directly to tumor cells.
    • Bispecific mAbs: Redirect T cells to kill tumor cells. Can also perform normal functions such as ADCC.

Conventional Mabs

  • Complement-mediated lysis and opsonization
    • C1+mAb+AntigenC1 + mAb + Antigen
  • FcR ADCC by macrophages or natural killer cells
  • Target cell Signaling, leading to apoptosis or growth arrest

Approved Conventional Mabs

  • Rituximab:
    • Chimeric anti-CD20 antibody.
    • Mechanisms: Apoptosis, ADCC, complement activation.
    • Used for relapsed and refractory follicular low-grade non-Hodgkin lymphoma (NHL).
    • Up to 6% complete response rate.
  • Herceptin (Trastuzumab):
    • Anti-Her2/neu antibody.
    • Mechanisms: Anti-proliferative effects, ADCC.
    • Used for advanced breast cancer with Her2/neu over-expression.
  • Erbitux (Cetuximab):
    • Anti-EGFR antibody.
    • Mechanisms: Anti-proliferative effects, apoptosis.
    • Used for irinotecan-failed advanced colorectal cancer.
  • Avastin (Bevacizumab):
    • Anti-VEGF antibody.
    • Mechanism: Neutralization of VEGF (vascular endothelial growth factor).
    • Used for advanced colorectal cancer.

Antibody-Drug Conjugates (ADCs)

  • A potent drug is attached to the antibody via a linker.
  • The conjugate travels in the blood to the tumor.
    • The linker must be stable to prevent premature drug release, which can cause severe toxicity.
  • The conjugate binds to a receptor on the tumor cell and is internalized.
  • The drug is released within the lysosome, killing the tumor cell.

Bispecific Mabs - Catumaxomab

  • Conventional antibodies have two identical antigen-binding sites.
  • Bispecific antibodies are created through genetic engineering by fusing two antibodies with different antigen-binding sites.
  • One antigen binding site recognizes the tumor, and the other arm recognizes a T cell.
  • The T cell is then redirected to kill the tumor cell.
  • Bispecific mAbs can still perform normal functions such as ADCC.

Bispecific Mabs – Blinotumomab Targets B Cell Leukaemia

  • Engineered binding site of an antibody (scFv) then link two together
  • Small (50-60kD), easy to produce and purify
  • Potent activity
  • No Fc so no effector function and rapidly excreted allowing only low amounts to reach the tumour
  • Administered via continuous infusion

Cancer and the Immune System

  • Elimination: As cells mutate, they are removed by the immune system, preventing cancer.
  • Equilibrium: Some mutations allow cells to avoid the immune system, but the immune system adapts, resulting in a balance (early-stage cancer).
  • Escape: Cancer evolves faster than the immune system can adapt, leading to tumor escape and progression (cancer).
    • Reference: Schreiber et al. (2011). Science 331(6024): 1565.

Overcoming Immune Evasion

  • Cancer evolves under immune pressure to avoid immune recognition.
  • Immunotherapy must reverse this balance.
  • Solutions:
    • Take the breaks off the immune system (checkpoint inhibitors).
    • Press the accelerator (cancer vaccines).
    • Both.

T Cell Fate Under Different Conditions of TCR Engagement

  • The slide illustrates T cell activation, inactivation, and enhancement using anti-CTLA-4 monoclonal antibodies (mAbs).
  • (A) T-cell Activation: Antigen presentation and costimulatory signals (TCR engagement with MHC and CD28 with B7) result in T-cell activation and proliferation.
  • (B) T-cell Inactivation: CTLA-4 expression is upregulated on T-cell surfaces, providing inhibitory signals to keep the immune response in check.
  • (C) Enhanced Activation with Anti-CTLA-4 mAb: Inhibiting CTLA-4 using monoclonal antibodies may activate/enhance the tumor-specific immune response.
    • MHC: Major histocompatibility complex
    • TCR: T-cell receptor
    • APC: Antigen-presenting cell

Ipilimumab (Yervoy) - Anti-CTLA-4

  • The slide likely shows a survival curve comparing Ipilimumab plus gp100, Ipilimumab alone, and gp100 alone.
  • Ipilimumab, an anti-CTLA-4 antibody, enhances T-cell activation and improves overall survival in melanoma patients.

Adverse Events in the Safety Population

  • The table provides a comparison of adverse events in patients treated with Ipilimumab plus gp100, Ipilimumab alone, and gp100 alone.
  • It includes total events, grade 3, and grade 4 adverse events.
  • The table lists both total and drug-related events, as well as immune-related events.

Nivolumab (Opdivo) and Pembrolizumab (Keytruda) – Anti-PD-1

  • Less toxicity as ligand is expressed by the tumour to avoid immune recognition
  • Both are approved for the treatment of melanoma and NSCLC (Non-Small Cell Lung Cancer).
    • Nivolumab is approved for all NSCLC.
    • Pembrolizumab is approved for PD-L1 positive tumors.
  • A combination of Nivolumab and Ipilimumab is approved for melanoma but is very toxic.

Checkpoint Inhibitors and Stimulators

  • Anti-CTLA-4 and anti-PD-1 are very effective in 20-50% of patients.
  • It is unclear if other checkpoint inhibitors/stimulators will be as effective or if there is synergy between them.
  • Problems:
    • They work on all T cells, not just cancer-specific T cells, therefore inducing autoimmunity (toxicity).
    • Only work if the tumor has instigated an immune response.
    • Reference: Mellman et al., Nature 2011 480:480

Vaccines

  • Prophylactic vaccines:
    • Stimulate antibody responses to prevent disease.
    • Example: HPV vaccine for cervical and head and neck cancer.
    • Stimulates an antibody response to the virus to prevent it from entering normal cells and inducing cancer.
    • Needs to be given before exposure to the virus.
  • Therapeutic vaccines:
    • Stimulate T cell responses to kill existing tumors.
    • T cells are the most important immune cells in killing tumors.
    • Stimulate de novo CD4 and CD8 T cell responses.
      • CD4+ (helper) T cells (Th1) can reverse the immunosuppressive tumor environment.
      • CD8+ (killer) T cells (CTL) directly kill tumor cells.
    • Problems:
      • Stimulate potent T cells that could overcome the immunosuppressive environment and kill tumors.
      • T cells recognizing self-antigens may have been deleted.

Mutanome: More Mutations, Better Immune Responses

  • This slide shows the prevalence of somatic mutations across different human cancer types.
  • The number of mutations per megabase is plotted on a log scale.
  • Cancer types with higher mutation rates (e.g., Melanoma, Lung Squamous) tend to have better immune responses.
  • Cancer types are ordered based on their median numbers of somatic mutations.

Vaccines – Tvec

  • T-Vec, Talimogene laherparapvec (Amgen)
  • Oncolytic virus injected into the tumor.
  • The virus replicates and kills tumor cells.
  • Needs to have an accessible tumor (skin cancer).
  • Very good response to the injected lesion but a weaker response to tumors that have spread to other organs (metastases) – most patients die of metastases.
  • Approved for Stage IV melanoma.
  • Combination studies with checkpoint inhibitors.

Vaccines -Neo-Epitopes

  • The slide seems to illustrate the process of identifying and using neo-epitopes in personalized cancer vaccines.
  • The process includes:
    • HLA haplotyping.
    • Exome and transcriptome sequencing of cancer tissue and PBMCs (as normal tissue).
    • Identification of cancer-specific SNVs (single nucleotide variants).
    • Prediction of potential neo-epitopes using tools like NetMHC.
    • Testing the ability of neo-epitopes to stimulate patient's T cells.
    • Synthesizing long peptides containing the neo-epitopes.
    • Immunizing the patient with a combination of peptides and a suitable adjuvant.

Adoptive T Cell Therapy -Tumour Infiltrating Lymphocytes

  • T-cells are collected from a tumor biopsy.
  • Reactive T cells are identified.
  • T cells are rapidly expanded in vitro (for 8 weeks).
  • Safety and efficacy are analyzed in vitro.
  • The patient is pre-treated with chemotherapy.
  • The cells are then returned to the patient along with supportive therapy.

Adoptive T Cell Therapy for Cancer – Technical Issues

  • Issues:
    • Low frequency of tumor-specific T cells.
    • No good tumor-specific antigen with which to select T cells.
    • Tumor loses antigen.
  • Process:
    • Collect T-cells from the patient.
    • Expansion of tumor-specific T cells.
    • T-cells returned to the patient.

TCR Modified T Cells

  • A T-cell that kills cancer is cloned from a patient who has rejected their cancer
  • The TCR is isolated and cloned into a virus which is then used to transduce T cells from a different cancer patient to arm their T cells to kill their cancer.

Chimeric Antigen Receptors (CARS)

  • References:
    • Eshhar Z (2010) Curr Opinion Mol Ther 12(1): 55-63
    • Bridgeman JS et al. (2010) Current Gene Therapy 10(2): 77-90

Chimeric Antigen Receptors (CARS)

  • The slide illustrates the structure of different generations of CARs:
    • First generation: scFv (single-chain variable fragment) + Linker + Hinge/spacer + Transmembrane domain + Signaling domain (zeta).
    • Second generation: Includes an additional costimulatory domain (4-1BB or CD28).
    • Third generation: Includes two costimulatory domains (e.g., 4-1BB and CD28).
  • scFv: single-chain variable fragment

Chimeric Antigen Receptors (CARS)

  • In a clinical trial, 30 children and adults received CTL019 CAR T-cell therapy.
    • Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation.
  • All patients experienced cytokine-release syndrome.
    • Severe cytokine-release syndrome developed in 27% of patients and was associated with a higher disease burden before infusion. It was effectively treated with the anti–interleukin-6 receptor antibody tocilizumab.
  • Approved CAR T-cell therapies:
    • Axicabtagene ciloleucel (KTE-C19, Axi-cel), marketed as Yescarta, for B-cell ALL in children and NHL in adults.
    • Tisagenlecleucel (Tisa-cel), marketed as Kymriah, for B-cell ALL in children and NHL in adults.

Summary

  • Early Tumors:
    • Vaccines (to stimulate an immune response).
  • Late Tumors:
    • Checkpoint inhibitors, CAR T cells, redirected T cells.
  • Non-toxic:
    • Oncolytic vaccines.
  • Combinations of vaccines and checkpoint inhibitors.
  • Toxic :
  • Potent T cell :
    • Overcome immune suppression