Shaping the future of cancer care

Cancer treatment strategies have progressed tremendously from the time when chemotherapy and radiation were the only available options for patients with inoperable tumours. Today, many treatment paradigms focus on a precision medicine approach to help ensure that patients receive the right treatment at the right time. Healthcare professionals (HCPs) now have an array of sophisticated options at their disposal to help patients live longer, including next-generation immunotherapies that galvanise the body’s natural defences and antibody-drug conjugates (ADCs) that precisely target tumours, as well as nuanced strategies to help prevent treatment resistance and disease progression.

While these innovations have produced breakthrough results in some types of cancer, many in the field believe that carefully designed combination therapies are the next frontier to help advance patient outcomes. By combining different treatment options – especially those involving immuno-oncology (IO) – researchers aim to develop approaches that can fight cancer from multiple angles, ultimately aiming to elevate standards of care.

One of the most significant therapeutic developments in cancer treatment over the last few decades has been immunotherapy, particularly checkpoint inhibitors like PD-1 and PD-L1 inhibitors. These agents work by preventing tumour cells from ‘switching off’ the immune response, thereby enabling the immune system to attack the cancer. For some patients, these medicines have been game changers, increasing survival while having fewer side effects than prior treatment options like chemotherapy.

However, not all cancers respond to immunotherapy, and treatment resistance can emerge in patients over time following initial response. Researchers believe this could be overcome by using multiple immunotherapies together – or by pairing IO with other treatment modalities, such as ADCs. In principle, this approach works to amplify the immune attack while simultaneously dismantling the various shields that cancer cells use to hide or adapt.

Yet the concept of combining immunotherapies requires careful balance. Broadly speaking, each immunotherapy medicine may trigger a different type of response from the immune system, so eliciting multiple responses simultaneously could risk significant side effects for the patient.

‘Cancer is the ultimate shapeshifter – tumours have an incredible array of mechanisms for hiding from immune cells’

A fine balance must be struck: sufficient immune activation to eliminate more tumour cells than with a single IO approach but not so much that patients experience unacceptable side effects.

A key driver of immunosuppression in cancer is the transforming growth factor (TGF)-β pathway. Under normal conditions, TGF-β is a signalling pathway that helps regulate tissue repair and immune tolerance, but tumours hijack this pathway to dampen immune responses and promote their growth. However, TGF-β is only one pathway in the immune system among a host of critical, interconnected pathways that cancers look to exploit. For example, TGF-β is known to drive regulatory T cells or Tregs that suppress anti-cancer immune mechanisms. Therefore, targeting the TGF-β pathway and Tregs within the tumour microenvironment, offers potential treatment strategies.

Closely linked to TGF-β is GARP (glycoprotein A repetitions predominant), a protein that activates TGF-β in the tumour microenvironment (TME) – the complex ecosystem that exists around tumours.

In the TME, TGF-β and GARP can act like a protective shield for the tumour, making it far harder for immune cells to penetrate the tumour’s defences. In principle, the concept of disrupting TGF-β/GARP could help unleash the immune system. Early-stage studies suggest that blocking GARP might enhance the tumour-killing capabilities of PD-1 inhibitors. By neutralising a key suppressive mechanism in the TME, immune cells have a better chance of recognising and attacking the cancer. Designing such medicines is challenging, as TGF-β plays many important roles in the body such as in heart and lung function. Nonetheless, precision-focused strategies – like antibodies or small molecules that only become active within the tumour – may limit off-target side effects elsewhere in the body and could make TGF-β/GARP inhibition a potential approach.

Similarly, for targeting Tregs specifically within the TME, it is important to identify markers or proteins that are highly expressed in TME Tregs. C-C chemokine receptor 8 (CCR8) is a protein that plays a crucial role in immune regulation and inflammation. CCR8 is a promising target due to its enhanced expression on tumour-infiltrating Tregs. A higher prevalence of CCR8 expressing Tregs (CCR8+ T regs) is associated with poor clinical outcomes in several solid tumour types. Therefore, depleting CCR8+ Tregs could offer a potential therapeutic approach to enable the immune system to fight cancer.

Despite the excitement around immunotherapies, results from recent IO-IO combinations have generally fallen short of initial hopes. While it may seem logical that two immunotherapies would prove more potent than one, we need to remember that success of a combination approach also depends on the safety aspects of combining immunotherapies. In addition to that, cancer is the ultimate shapeshifter. Tumours have an incredible array of mechanisms for hiding from immune cells. When one checkpoint is blocked (like PD-1), the tumour may switch to another pathway (such as LAG-3, TIM-3).

The immune system is a collection of delicate checks and balances in which over-activation can lead to serious side effects for the patient. Therefore, the challenge remains determining which immunosuppressive pathways to inhibit – and in what sequence – to avoid triggering an immune system ‘storm’ response. Researchers are looking for biomarkers that predict a patient’s likely response to combination immunotherapy, hoping that this will allow for a more personalised and effective treatment approach. Oncologists could also vary the order in which medicines are given, using one agent to prime the immune system and a second to amplify the impact.

Several clinical trials have now explored these important considerations. Although the overall progress towards IO-IO combination therapies may be slower than expected, the scientific consensus remains optimistic – if the right targets are identified and side effects can be managed, IO-IO combinations could be pivotal for patients who currently see marginal benefit from single immunotherapies.

Beyond IO-IO pairings, another promising approach is combining antibody-drug conjugates (ADCs) with immunotherapies. ADCs are engineered to deliver potent chemotherapy payloads straight to cancer cells. Unlike conventional chemotherapy, which affects both healthy and malignant cells, ADCs are designed to zero in on molecular markers found primarily on tumours. Once an ADC is internalised by the tumour, it releases a cytotoxic drug, effectively killing the cell from within.

ADCs can spark a form of cancer cell death that ‘flags’ the tumour for further immune scrutiny. In other words, dying cancer cells can release signals – like tumour antigens and cytokines – that summon immune cells to the battlefield. When an ADC is paired with a PD-1 or PD-L1 inhibitor, the elimination of the tumour may be supercharged. Early-stage clinical trials evaluating ADC-immunotherapy combinations have been encouraging, especially in solid tumours that historically resist single-agent immunotherapy. Researchers are now exploring dose optimisation, and evaluating whether the ADC should be given first to ‘soften up’ the tumour before immunotherapy, or whether both should be administered simultaneously.

Challenges do remain, though. For instance, if an ADC is too potent or non-specific, it can harm healthy tissue and cause inflammation that interferes with immunotherapy. Tumours can also reduce the expression of the targeted biomarker over time, potentially rendering the ADC less effective. Despite these hurdles, ADC-immunotherapy pairings represent a bold new direction in cancer care, offering a way to target both the tumour cells and the TME in a coordinated plan of attack.

In today’s oncology landscape, the ultimate goal is not merely to reproduce the incremental improvements seen in recent decades but deliver a shift towards personalised, durable treatments that deliver both improved patient care and outcomes. A patient-centred ethos drives research at every level – from identifying more precise biomarkers to designing clinical trials that track patient quality of life. Indeed, breakthroughs in computational biology and genomic analysis have given scientists unprecedented insight into the molecular underpinnings of each patient’s tumour, potentially guiding oncologists to more effective, less toxic personalised treatment options.

The future may therefore involve ‘smart’ sequencing of multiple medicines and technologies. With each year, researchers uncover new targets and refine combination strategies in a bid to outmanoeuvre cancer’s adaptive mechanisms. In that sense, the field is both expanding – embracing more sophisticated science – and focusing – centring squarely on what works best for patients. As scientists further decode the signals between tumours, immune cells and the broader body, a future where advanced treatment combinations transform stubborn cancers into more chronic diseases comes ever closer. And that holds immense promise for individuals and families touched by this disease.

References are available on request.

Pedro Valencia is VP, Asset Strategy Leadership, Oncology at AbbVie