Timeline of Immunotherapy

By Robyn Please
  • 130 BCE

    Greek physician Claudius Galen

    first suggested cancer might develop from inflamed wounds, following accounts of tumour regression after infections. Oncology stems from Galen describing tumours as ‘oncos’; Greek for swelling (6).

  • Wilhelm Busch and Friedrich Fehleisen

    observed spontaneous tumour regression in erysipelas bacterial infected individuals, suggesting the immune system modulated cancer (6)

  • Dr William Coley is considered ‘the father of immunotherapy’

    after carrying out the first immunotherapy treatments. He injected many cancer patients with bacterial products, now called ‘Coley toxins’, and thought immune activation against the bacterial infection caused the observed tumour shrinkage (7). Unfortunately, lack of evidence and acceptance prevented these from common use (2)

  • Tumour-associated antigens

    (proteins on cancer cells) were discovered, creating potential targets for cancer therapy (8).

  • Interferon (IFNγ)

    Interferon (an immune system signalling molecule) was discovered and showed effectiveness against cancer (9)

  • Lewig Thomas and Macfarlane Burnet,

    first proposed the cancer immunosurveillance hypothesis (10). This suggests the immune system constantly patrols and protects our body by destroying foreign or abnormal cells such as cancer. Cancer can develop if this system fails.

  • T and B lymphocytes characterised

    and their role in cancer specific immune responses (11, 12). These are the two major cells of the adaptive immune system, which can eliminate infections or abnormal cells directly or through production of antibodies. They also create long-term memory so a rapid immune response can be mounted if detected again.

  • IL-2 discovered

    (a factor which stimulates T-cell activity). This enhanced understanding of how T-cells function in immune responses, presenting a method for enhancing anti-tumour response (13).

  • - First successful bone marrow transplantation from an unrelated donor

    This can be classed as immunotherapy as the transplanted donor immune cells can mount a response against and destroy the recipient’s cancer cells; a phenomenon called Graft vs Leukaemia effect (14).

  • T-cell leukemia virus discovered

    supporting the theory that viruses can cause cancer (15).

  • Studies of AIDs patients developing Kaposi’s sarcoma

    enhanced understanding of compromised immune systems resulting in cancer development (16).

  • First effective immunotherapies using IL-2

    were administered and showed curative effects, highlighting the power of manipulating T-cells for cancer destruction.

  • - First cytokine immunotherapy for Hair-cell leukaemia FDA-approved

    using interferon-alpha-2 (IFNa2) which targets a signalling molecule that eliminates viral infections (17).

  • Jean-Francois Brunet

    discovered the first immune inhibitory checkpoint molecule; CTLA-4, which inhibits T-cell activation to regulate immune responses (18)

  • The bacterial vaccine immunotherapy, BCG

    was FDA-approved for bladder cancer (19)

  • Discovery of PD-1

    thought to mediate apoptosis (20)

  • Pioneering study by Alison

    showed that blocking CTLA-4 with monoclonal antibodies successfully cured cancers in mice (21). Honjo and colleagues identified PD-1 as a T-cell inhibitory checkpoint (22)

  • Cancer-testis antigen

    (a protein usually present on normal cells, except the testis) was found on many cancer cells, presenting a target for immunotherapy (23).

  • - The first anti-CTLA-4 ICI drug (Ipilimumab), was FDA-approved for advanced melanoma

    following Dr. James Alison’s pioneering study and clinical trials showing significantly improved survival rates (24). It’s approved for many other cancers.

  • - Science magazine named immunotherapy ‘breakthrough of the year’

    highlighting its potential, particularly ICIs and CAR-T cell therapy (25).

  • - First oncolytic virus immunotherapy was approved for melanoma (27).

    This uses viruses modified by scientists to better target cancer cells and induce an anti-cancer immune response, without harming healthy cells. Many others are under clinical trial(28).

  • First FDA-approved combination immunotherapy involving two ICIs:

    ipilumumab (anti-CTLA-4) and Nivolumab (anti-PD-1), for advanced melanoma (26).

  • First anti-PD1 ICI

    pembrolizumab, approved for melanoma (29)

  • First CAR-T cell (adoptive cell transfer) immunotherapy approved

    This modifies patient’s T-cells in a laboratory to better target cancer cells upon re-administration (30).

  • A novel drug delivery system

    using an inflammatory signalling molecule, IL-12, shows ability to make un-responsive cancers more responsive to immunotherapy (31).