CAR T-cell therapy in oncology: The road ahead

 

CAR T-cell therapy has emerged as a ground-breaking advancement in the treatment of cancer, offering hope to patients with certain types of cancers that are resistant to more conventional therapies. By genetically modifying a patient’s own T cells to recognise and attack cancer cells, this immunotherapy has demonstrated remarkable success, leading to long-term remissions in conditions such as leukaemia and lymphoma. However, despite its potential, this new treatment method is not without its challenges.

In the article below, Porterhouse Medical shines a spotlight on the CAR T-cell therapy, the successes and challenges of this treatment, and the road ahead as research continues to evolve.

What is CAR T-cell therapy?       

Chimeric antigen receptor (CAR) T-cell therapy is a type of immunotherapy that has been extensively researched and applied to the field of oncology. The process involves collecting patient blood and extracting T cells in the lab. T cells are a type of white blood cell that help the immune system to combat infection and disease. Once extracted, the T cells are genetically engineered to express synthetic receptors that will target a specific tumour antigen [1]. These reprogrammed T cells are then encouraged to proliferate before being reintroduced into the same patient, activating a powerful immune response that will specifically target the antigen-expressing tumour cells for elimination [1]. CAR T-cell therapies are widely used to treat certain types of haematological malignancies, including B-cell acute lymphoblastic leukaemia, relapsed/refractory B-cell lymphomas and multiple myeloma [2].

What are the successes?

Clinical trial results for CAR T-cell therapies treating haematological malignancies have been extremely promising, showing impressive complete response, remission and overall survival rates both initially and in long-term follow-up studies [3–5]. Results have been so successful that the US Food and Drug Administration (FDA) has approved five other CAR T-cell therapies since the first approval in 2017; three of these are also recommended by the National Institute for Health and Care Excellence (NICE) [6–8]. An advantage of CAR T-cell therapies is that they have been shown to be successful in treating patients with relapsed or refractory blood cancers that had not responded to previous treatments or transplants [9]. Additionally, CAR T-cell therapy typically only requires a single infusion and 2–3 weeks of inpatient care compared with other types of cancer treatments; for example, chemotherapy requires multiple cycles with 4–8 weeks of recovery per cycle [10, 11].

What are the challenges?

Despite the successes of CAR T-cell therapies, there are still several challenges that need to be addressed. First, treatment-related toxicities have been reported in several CAR T-cell therapy clinical trials; the most common of these toxicities are cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) [12]. CRS involves vastly increased levels of circulating cytokines secreted from both CAR T cells and activated immune cells. ICANS is when these cytokines infiltrate the cerebrospinal fluid owing to disruption of the blood–brain barrier. Both CRS and ICANS can cause life-threatening symptoms. Unfortunately, cytokine release is required for clinical efficacy of CAR T-cell therapies, so it is essential for researchers to try to strike a balance between efficacy and toxicity [12]. Other toxicities that can occur following CAR T-cell treatment are dubbed ‘on-target, off-tumour effects’, where CAR T cells interact with target antigens expressed by non-malignant cells, causing eradication of healthy cells [13]. Another challenge to CAR T-cell therapies is ‘antigen escape’, in which the cancer cells develop resistance by mutating to no longer express the target antigen. This phenomenon has been observed in a sizeable number of patients, leading to relapse in long-term follow-up studies [14]. Furthermore, clinical trials in CAR T-cell treatment of solid tumours have produced disappointing results so far. These can be attributed to a multitude of factors, including the immunosuppressive microenvironment, physical barriers, and the antigen heterogeneity typically expressed by solid tumours [15]. Outside of efficacy and toxicity challenges, there are also challenges with the manufacturing process of CAR T cells. For patients with relapsed/refractory disease, having to wait 3–4 weeks for CAR T cell production can be too long. An example of this is the ELIANA trial, where death, deterioration or manufacturing issues prevented 18% of patients from receiving treatment [16].

How can challenges be addressed?

The structural engineering of CAR T cells is constantly being evolved to overcome challenges by improving efficacy or reducing toxicity. For example, new generations of CAR constructs have been designed to target multiple tumour-associated antigens in an attempt to overcome antigen escape and reduce relapse rates [17]. In terms of systemic cytokine toxicities, improvements in clinical management such as standardised grading scales and treatment guidelines have been created so that these toxicities can be recognised and treated. This is typically carried out using drugs inhibiting the proinflammatory cytokine interleukin 6 pathway, which has been associated with cytokine pathogenesis [18]. Additionally, some CAR constructs have now been developed to also include control switches or ‘suicide genes’ that can deactivate the CAR T cells if cytokine toxicities or ‘on-target, off-tumour effects’ occur [19]. CAR T-cell treatment for solid tumours continues to elude researchers, but several studies investigating potential strategies to overcome the existing challenges are ongoing. One potential strategy is to target immunosuppressive cells within the tumour microenvironment to increase CAR T-cell efficacy. Other strategies include using local infusion techniques to administer CAR T cells directly into tumours to overcome the physical barriers and modulating chemokine signalling to enhance CAR T-cell trafficking to solid tumours [20]. Instead of having to genetically engineer patient cells on an individual, case-by-case basis, next-generation CAR T cells aim to be mass produced using healthy donor cells, to help reduce the length of the manufacturing process [21].

Despite the challenges that still exist with the utilisation CAR T-cell therapies, clinical results thus far have been promising, with the therapies even appearing to have curative effects in subsets of patients who were otherwise unresponsive to previous treatments. Looking forward, there are numerous strategies undergoing investigation to address these challenges and pave a promising future for CAR T-cell therapies, offering greater hope in the fight against cancer.

At Porterhouse Medical, we are passionate and knowledgeable about oncology, working on a variety of projects to improve treatment options and patient outcomes through healthcare communications and insights.

If you are interested in finding out about the services offered by Porterhouse Medical, please visit porterhousemedical.com/our-approach/ or contact mark.walker@porterhousemedical.com. We would love to hear from you!

References

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Author:

Saffron Goldsworthy Ι Intern Ι Porterhouse Medical