ROGER EXPLORES… Immunotherapy

by Roger Wilson

Immunotherapy is a fast-changing area of research being pursued in a wide range of ways by clinical researchers and scientists from all kinds of backgrounds.  Lots of hopes are pinned on the benefits of these novel therapeutic approaches for cancer patients.

Yet, when we analyse what is coming out from current studies, there is actually very little which directly impacts on sarcoma treatment. It is clearly an area which is challenging.  We know that immunotherapy treatments for advanced sarcoma rarely have long-lasting benefit for our patients unlike those for many other cancers.

Let’s start with T-cells. Everyone has them. They are the heart of our natural immune system. They do the job of getting rid of unwanted invaders (such as bacteria) and many cellular mutations, which happen all the time quite naturally. A cancer is a cellular mutation that gets out of hand. It learns how to evade the T-cell, to hide itself from the natural cure. Therefore, enabling T-cells to see cancer cells and to tackle them effectively is a primary aim of this area of research.

The methods which have been developed and brought into use in other cancers have relied heavily on being able to edit genes. CAR-T therapy stands for Chimeric Antigen Receptor T-cell and is based on taking a sample of patient T-cells, editing them genetically, growing them to a significant volume which can be infused back to the patient, and letting them take over the immune system in the patient. There can be severe side effects, though generally well-managed. It is clearly a one-patient process but is now being done in significant numbers in lymphoma and leukaemia patients.

This approach has been used effectively in synovial sarcoma when a specific protein - the Melanoma-associated Antigen A4 (MAGE-A4) protein - is present. This T-cell receptor (TCR) therapy uses Afamitresgene autoleucel. It was trialled internationally in 44 patients with advanced disease. 17 of them responded with a median remission of 6 months. The US regulator for medications, the Food and Drug Administration (FDA), approved the therapy and more research is underway as the benefit versus burden balance is very uncertain. (1)

Another approach is known as BiTE - Bispecific T-cell engager.  These are laboratory-engineered molecules which have two binding sites: one that attaches to a specific T-cell protein and another that binds to a tumour-specific antigen on the cancer cell surface. The physical link that the BiTE engager creates activates the T-cells to kill the cancer cells. This process is being used to treat various blood cancers. A trial addressing the New York esophageal squamous cell carcinoma-1(NY-ESO-1) protein found in synovial sarcoma and myxoid liposarcoma used the bispecific antibody and T-Cell engager DS-2243 was reported at the 2025 meeting of the American Society of Clinical Oncology (ASCO). (2)

Then, there are also the so-called Checkpoint inhibitors. Checkpoints are proteins on T-cells which govern their activity.  These can switch off T-cells, when they should really be attacking the cancer cells - like pushing a stop button on the immune system so the T-cells can no longer recognise and kill cancer cells. Checkpoint inhibitors stop the proteins on the cancer cells from pushing the T-cell stop button. This turns the immune system back on and the T-cells are able to find and attack the cancer cells. One of the best known of these treatments, pembrolizumab, works on a specific protein, the PD-1 (Programmed Cell Death Protein 1) which has been found in some sarcoma patients. It is not however an approved treatment for sarcoma - so, where it has been used, exceptional funding approvals had to be given. (3)

Oncolytic viral research is developing as another means of immunotherapy. Viruses are particles that can infect cells and can reproduce themselves spreading to uninfected cells. Some viruses like the Human Papillomavirus (HPV) can cause cancer. Developing viruses to be injected to treat cancer is a logical idea. Oncolytic viruses are engineered to deliver therapeutic payloads to tumours, ignoring healthy cells and producing immune-boosting molecules once they infect the tumour. It is hoped that they can also stimulate the natural immune system to copy what is happening and search and destroy cancer cells elsewhere in the body.  In sarcoma, these viruses are at a very early stage of development with Phase-1 first-in-man studies underway.

While not strictly immunotherapy, it is worth mentioning some other related treatment developments which will appear in the sarcoma medical oncology armamentarium.

An Antibody drug conjugate (ADC) is a targeted cancer therapy that combines a monoclonal antibody (a biologic treatment) with a cytotoxic drug (the payload) via a chemical linker. The antibody acts like a "guided missile," targeting and binding to specific proteins on cancer cells, which allow the ADC to be absorbed into the cell. Once inside, the linker releases the potent chemotherapy drug to kill the tumour cell while minimizing damage to healthy cells.

Lastly, tumour agnostic drugs are already appearing. They target genetic mutations which appear in several different cancers. Larotrectinib is already approved for cancers with the Neurotrophic Tyrosine Receptor Kinase (NTRK) gene fusion, which includes some rare fibrous sarcomas. (4)

Some specific immunotherapies may also become more generally applicable as clinical research tests them in cancer types for which they are not initially approved. This applies to pembrolizumab, noted above.

This is an area where sarcoma patients may benefit - re-purposing treatments which are approved for other cancers, but which have shown some promise for treating sarcoma. Becoming a tumour agnostic treatment, whether targeting a specific gene, or acting more generally, with evidence provided through both exceptional clinical use and formal trials is an important area for development. This re-purposing is being encouraged by the European Commission and European Medicines Agency (EMA), with new regulatory methods open to patient groups, academic scientists and charities.

At our forthcoming SPAGN annual meeting in Stockholm from 1 – 3 May 2026, we will have a presentation and discussion on genetics and treatment.  My colleague Dr. Ornella Gonzato has written a great pre-reading piece for those who want to dive deeper. You can find it here.

 

 

References:

(1) D'Angelo S, Araujo D, Abdul Razak A et al. Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial. The Lancet, 2024; 403, 1460-1471 

(2) D’Angelo S, Subbiah V, Blay, J.Y. et al. A phase 1, first-in-human study of DS-2243, an HLA-A*02/NY-ESO–directed bispecific T-cell engager, in patients with advanced solid tumors. Journal of Clinical Oncology,TPS2668(2025) Volume 43, Number 16_suppl

(3) Watkins J, Trotman J, Tadross J et al. Introduction and impact of routine whole genome sequencing in the diagnosis and management of sarcoma. British Journal of Cancer, 131, Article 5.

(4) Efficacy and safety of larotrectinib as first-line treatment for patients with TRK fusion cancer. ESMO Open, 2025; 10

 

Credits:  Graphic design by Karl Berger