4.3 Oncology treatment: Immunotherapy

The immune system

The immune system can play an important role in the treatment of cancer.

The body’s immune system can effectively fight foreign or abnormal cells in the body, such as allergens, viruses and bacteria. The immune system can also recognise cancer cells as foreign cells. However, the immune system doesn’t react sufficiently to the cancer cells in order to eradicate them. This is because cancer cells can protect themselves by using various mechanisms that can counteract immune attack (e.g. express PD-L1 on their surface).

Definition of immunotherapy

Immunotherapy is a form of treatment that uses the body’s own immune system to target the cancer. You can activate the immune system either by stimulating the immune cells or by blocking the immune system’s braking mechanisms (immune checkpoints: cytotoxic T-lymphocyte associated antigen (CTLA-4), programmed cell death protein 1 (PD-1) and programmed death ligand 1(PD-L1)).

In other words, the treatment must:

  • Strengthen the immune system’s ability to recognise and attack cancer cells
  • Impair the ability of cancer cells to defend themselves

Immunotherapy is based on various mechanisms:

  1. Cytokines
  2. Checkpoint inhibitors
  3. Adoptive T-cell therapy
  4. Vaccines

Cytokines – IL-2 based immunotherapy

Immunotherapy has been involved in mRCC for many years. Interleukin-2 (IL-2) was identified in 1976, cloned in 1983 and approved for the treatment of mRCC by the Danish authorities in 1989 and the FDA in 1992.
IL-2 binds to the IL-2 receptor on the immune cells, particularly T cells and natural killer (NK) cells, thereby activating and carrying out tumour destruction.

Interferon alpha (IFN-α) was identified in 1957, cloned in 1980 and first used in 1983 in patients with mRCC. The working mechanism is an anti-proliferative tumour effect, activation of certain immune defence cells, and an increase in the antigen presentation of the tumour cell.

The combination of IL-2 and IFN-α is an approved treatment option for patients with clear-cell-type mRCC. IL-2 can be given as high (intravenous), intermediate (subcutaneous) and low (subcutaneous) doses. There are more adverse reactions to high-dose IL-2, but probably also better efficacy.

After the approval of targeted treatment and checkpoint inhibitors for the treatment of patients with mRCC, IL-2-based immunotherapy is only rarely used. High-dose IL-2 remains a treatment option for selected patients with mRCC 1,2,3

Immunocheckpoints

Immunocheckpoints are proteins important for maintaining immunological homeostasis;
immunocheckpoints are membrane proteins expressed on the surface of antigen-presenting cells and on T-cells. The inhibitory immune checkpoints such as CTLA-4 and PD-1 slow the immune response by shutting down the activation of T cells. The activating immune checkpoints are present to start and maintain an immune response. The inhibitory immune checkpoints are important in protecting against autoimmunity and in protecting cells from damage when the immune system responds to infections.

CTLA-4 and PD-1 exert their regulatory effect in different stages of an immune response4.5:

  • CTLA-4 is primarily expressed on naive T-cells in the lymph nodes (priming phase), and interaction between CD80/CD86 on the antigen-presenting cell (APC) and CTLA-4 leads to inhibition of the T-cell
  • PD-1 is primarily expressed on activated T-cells. The ligand, programmed death ligand 1 (PD-L1), is expressed on dendritic cells and macrophages, but may also be expressed on cancer cells. PD-1 stimulation regulates negatively activated T-cells in a later stage of the immune response – primarily in the peripheral tissue (effector phase)

Checkpoint inhibitors7

Cancer cells can manipulate the immune system via immune checkpoints by e.g. up-regulation of PD-L1, leading to inhibition of the T-cells and prevention of tumour cell killing.

Checkpoint inhibitors are monoclonal antibodies that block the interaction between
CTLA-4 and CD80/CD86 and PD-1 and PD-L1, respectively. This releases a brake on the immune system and creates the possibility of initiating or reinforcing an already activated immunological reaction directed at the tumour cells.

Medicinal products

Adoptive cell therapy

Adoptive cell therapy consists of infusion of live T-cells that can recognise and kill cancer cells. The infused T-cells can be divided into 3 types:

  1. Tumour-infiltrating lymphocytes (TIL) extracted from the patient’s own tumour
  2. Genetically manipulated T-cells with chimeric antigen receptor (CAR)
  3. T cells, with genetically manipulated T cell receptors that recognise specific antigens

T-cell therapy3.4

Malignant tumours are often infiltrated with T-cells – so-called TILs. TILs can specifically recognise tumour antigens, but are often inactive due to an immunosuppressive microenvironment. T-cell therapy based on TIL expansion is an experimental treatment consisting of infusion of the patient’s own T-cells that are ex vivo propagated and activated. The treatment is highly specialised and takes place in DK only at the Centre for Cancer Immune Therapy (CCIT) at Herlev Hospital.

Adoptive T-cell therapy: A surgeon removes tumour tissue, which is then cut into small fragments and placed in culture dishes. The immune-stimulating cytokine interleukin 2 is added so that the T-cells expand into several billion T-cells. Prior to intravenous infusion of the patient’s own T-cells, the patient is pretreated with lymphodepleting chemotherapy.

C = cyclophosphamide; F = fludarabine phosphate; I = after infusion of the T cells, treat with IL-2; IL = interleukin; TIL = tumour infiltrating lymphocytes.
Reproduced with permission from Professor Inge Marie Svane, June 2019.

Promising results have been seen in patients with disseminated malignant melanoma. It is being investigated whether the same results can be achieved in patients with mRCC. Below is a diagram illustrating the process from tumor tissue removal to its propagation, activation, and subsequent infusion back into the patient.

Combination of checkpoint inhibitors and TKI

Promising results have been observed with several different combinations of anti-PD-1/anti-PD-L1 together with VEGFR/VEGF inhibition (TKI/Bevacizumab) with good response rates, improved mPFS and mOS. Several combinations have now been approved abroad, but not yet in DK.

References

  1. DaRenCa guidelines
  2. Overall survival by clinical risk category for high dose interleukin-2 (HD IL-2) treated patients with metastatic renal cell cancer (mRCC): data from the PROCLAIMsm registry. Fishman et al. J Immunother Cancer. 2019.)
  3. Current status and future directions of immunotherapy in renal cell carcinoma. Considine B & Hurwithz M Curr Oncol Rep. 2019.
  4. Cancer immunotherapy, Kjelden JW et al. The Danish medical journal, Ugeskrift for læger. 2018
  5. Tumour Immunotherapy Directed at PD-1. Ribas A. NEJM 2012.)
  6. Immunotherapy is cancer treatment with a completely new adverse reaction profile. Kondrup et al. The Danish medical journal, Ugeskrift for læger. 2017.
  7. Ribas A. NEJM 2012

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