Cancer develops insidious strategies to bypass the action of the immune system, responsible for destroying malignant cells in their initial stages. For some decades, several lines of research (1) have tried to unravel the repression that cancer imposes on the immune system.
These strategies are known generically as anticancer immunotherapy. So far, spectacular successes have been achieved in people with end stage tumours.
The increased survival of people with advanced cancer has been the subject of an editorial in JAMA, titled “Oncology in Transition, Changes, Challenges, and Opportunities” (2).
Immunotherapy is responsible for this increased survival in severely life-threatening situations. However, the side effects of these treatments are important, and the economic costs should perhaps be considered as another «side effect», not exactly minor.
Limited experience, both in terms of time and the number of patients, indicates that the immunotherapy works in approximately half of the patients (3). However, in cases where the response is favourable, truly impressive recoveries are achieved.
Will immunotherapy be the long-awaited solution to cancer? Probably do not. However, hundreds of clinical trials are currently underway (4), and research is trying to tailor already marketed therapies for maximum benefit, while looking for new ones.
So far, the two versions of anticancer immunotherapy approved by the US Food and Drug Administration (US-FDA) are the so-called «checkpoint inhibitors» (technically «PD-1 inhibitors») [5], and CAR- cells T (Chimeric Antigen Receptor-T) [6]. T cells, one of the two fundamental strains of the immune system, are involved in both strategies.
A novel line of research is directed at another type of immune cell: macrophages.
Macrophages are mononuclear phagocytic cells much larger than the monocytes from which they are derived and with an average life of between 2 and 4 months. They are ubiquitous, being present in all organs and tissues, where they receive particular names depending on the tissue or organ: Kupffer cells (in the liver), histiocytes (connective tissue), microglia (nervous tissue), etc. Macrophages can remain relatively immobile or move amoeboid.
Macrophages, in addition to their phagocytic activity (previous opsonization), secrete cytokines that attract neutrophils to the site of inflammation, act as «antigen presenting cells» (7) for T cells, being in turn activated by interferon gamma (IFN -γ) secreted by T-helper cells (helper T cells).
Major histocompatibility complex class II (MCH-II) proteins are expressed on the membrane of active macrophages, as opposed to resting macrophages. [MHC was discovered by Jean Dausset who originally named them HLA, Human Leucocyst Antigen, because he thought they were characteristic of white blood cells. This discovery was recognized Nobel Prize in Physiology or Medicine in 1980, ex aequo Baruj Benacerraf and George Snell].
Activated macrophages also express the CD11 receptor, and opsonins (host proteins that signal pathogens or foreign macromolecules making them vulnerable to phagocytosis).
[CD11, whose genotype is 16p.11.2, is expressed on neutrophils, monocytes (macrophage precursors), NK (Natural Killers), and activated T and B cells. CD11 is a type 1 transmembrane glycoprotein that associates with CD18 to form β2-integrin-p150 (complement receptor). It binds with iC3b (a complement protein), LPS (Lipopolysaccharide), ICAM-1 (Inter-cellular Adhesion Molecule type 1), fibrinogen and other ligands related to the inflammatory process].
Interferon-gamma (INF-γ) stimulates the transcription of MHC-II genes (major histocompatibility complex class 2).
All the aforementioned processes prepare macrophages to present antigens to T-helper lymphocytes. In addition, macrophages determine the differentiation of Th lymphocytes: interleukin-10 (IL10) stimulates Th2 lymphocytes; and IL-2 stimulates Th1 lymphocytes.
On the other hand, the antitumor activity of macrophages is mediated by the secretion of Tumour Necrosis Factor-α (TNF-α).
However, excessive and prolonged activation of macrophages can be harmful by acting against components of the body itself, a kind of «friendly fire.»
Cancer cells activate a biological switch that turns macrophages off, disabling them to first target and then engulf tumour cells. In addition, cancer cells express a protein (CD47) that inhibits the action of macrophages. [CD is acronym of Cluster of Differentation].
The New England Journal of Medicine has published a study (“CD47 Blockade by Hu5F9-G4 and Rituximab in Non-Hodgkin’s Lymphoma”) [8] in which took part 22 patients with lymphomas refractory to conventional treatments. The patients were treated with Rituximab and an experimental drug (Hu5F9-G4) that blocked the CD47’ membrane protein. The trial has been financed by the manufacturer of the experimental drug. [CD47 is also designated IAP (Integrin Associated Protein), whose genotype is 3q13.1-q13, and is expressed in haematopoietic, epithelial, endothelial and sperm cells. It binds to PTP (Protein Tyrosine Phosphatases) receptors; regulates the entry of Ca2 + after the adhesion of extracellular molecules to the outer membrane; activates neutrophils during innate response; and prevents premature expression of auto RBCs (Red Blood Cells)].
In eight patients, the cancer resolved completely; in another 11 there was a very significant improvement. Side effects were considered acceptable in relation to other forms of immunotherapy.
It cannot generalize about this approach, but other trials are being planned in various cancers, including multiple myeloma.
The pharmacological intervention on macrophages is conceptually identical to that used on T cells: deactivating the mechanism that turns off the immune system.
The «checkpoint inhibitors» («PD-1 inhibitors») block the off switch of the T cells, leaving them in a position to fight against tumour. The first drug in this class was Ipilimumab (Yervoy®), authorized in 2011; the next one was Nivolumab (Opdivo®), approved in 2014; since then ten other drugs have followed.
The two researchers who identified the checkpoints of immune cells, whose blocking has opened ways to fight against cancer, have been awarded the 2018 Nobel Prize in Physiology or Medicine. They are the American James Allison, who identified the CTLA-4 checkpoint (acronym for Cytotoxic-T Lymphocyte Antigen-4), and the Japanese Tasuka Honjo, who found checkpoint PD-1 (acronym for Programmed Death).
The immediate goal of cancer immunotherapy is to achieve that the results to be predictable and work for the largest number of patients. Until now, the strategy consists of combining drugs that act on different checkpoints or associating immunotherapy with conventional chemotherapy. In some cases, truly extraordinary remissions have been achieved, such as melanoma with brain metastases, and «triple-negative» breast cancers.
CAR-T cell immunotherapy is much more complex. In this case, millions of T cells are extracted from the patient, genetically reprogrammed to activate them against a specific target of cancer cells. After their in vitro culture, a huge number of them are injected back into the patient. The first patient to benefit from this therapy was Emily Withhead, a 6-year-old girl from Philadelphia, United States, in 2012, affected by childhood leukaemia refractory to conventional treatments. At present, the girl, already 16 years old, continues healthy without having suffered a relapse of her disease.
In 2017, two CAR-T immunotherapy treatments were approved: Tisagenlecleucel and Axicabtagene ciloleucel [9], both for the treatment of certain types of leukaemia and lymphoma.
Current research tries to validate these treatments in the therapeutic approach of solid tumours. The work is hard; uncertain results; the immense hopes.
Bibliography.-
- López-Tricas JM., Álvarez-de-Toledo-Bayarte, A. Immunotherapy for the treatment of cancer. European Journal of Clinical Pharmacy 2017; 19(6): 355-358.
- Schrag D., Basch E. Oncology in Transition. Changes, Challenges, and Opportunities. JAMA 2018; 320(21): 2203-4.
- López-Tricas JM., Álvarez-de-Toledo-Bayarte, A. Immunotherapy for cancer: how and when? European Journal of Clinical Pharmacy 2018; 20(2): 59-61.
- López-Tricas JM., Álvarez-de-Toledo-Bayarte, A. Oncological Immunotherapy: Clinical Studies? European Journal of Clinical Pharmacy 2018; 20(1): 3-4.
- López-Tricas JM., Álvarez-de-Toledo-Bayarte, A. PDL-1 Inhibitors: strategy or tactic? European Journal of Clinical Pharmacy 2016; 18(4): 211-213.
- CAR-T Cells: Engineering Patient’s Immune Cells to Treat Their Cancers. National Cancer Institute. In: https://www.cancer.gov/search/results. Consult: January 2019.
- López-Tricas JM. Células presentadoras de antígenos. http://www.info-farmacia.com/bioquimica/celulas-presentadoras-de-antigenos. In: info-farmacia.com. Consult: January 2019.
- Advani R. CD47 Blockade by Hu-5F9-G4 and Rituximab in Non-Hodgkin’s Lymphoma. N Engl J Med 2018; 379: 1711-21.
- López-Tricas JM., Álvarez-de-Toledo-Bayarte, A. Axicabtagene ciloleucel gene therapy for non-Hodkgin lymphoma. European Journal of Clinical Pharmacy 2018; 20(3): 123-125.
Zaragoza, October 2021
López-Tricas, JM
Hospital Pharmacy
Zaragoza (Spain)