For past generations of cancer patients, the foundations of their treatment has been surgery, chemotherapy and radiation therapy. Current advances in cancer care however are now being driven forward by the utilisation of a patient’s immune system to unleash antitumour activity in combination with targeted therapies which aim to inhibit molecular pathways that are crucial for tumour growth and maintenance.
The Cancer Immunity Cycle
The key steps involved in the promotion of an antitumour immune response have been termed as the ‘cancer-immunity cycle’. Anticancer T cell responses are initiated when tumour antigens are captured and processed by dendritic cells in the tumour micro-environment. These dendritic cells travel to tumour-draining lymph nodes, where they prime naïve T cells to become effector T cells which are capable of killing cancer cells. Once these T cells have infiltrated the tumour, they in turn trigger additional antigen release that has the potential to induce further rounds of anticancer immunity.
As seen in Figure 1, VEGF inhibitors complement T cell checkpoint therapies by enhancing dendritic cell maturation and activity, as well as T cell infiltration into tumours. MAPK inhibitors on the other hand work by enhancing tumour antigen expression, immunogenic tumour cell death and T cell tumour infiltration.
There are currently a significant number of planned or ongoing studies aimed at combing targeted therapies with immunomodulatory therapies. In fact, in some cases there has been evidence that shows targeted therapies are also able to enhance aspects of the cancer-immunity cycle thereby providing further rationale for their combined use.
T cell activation is a multistep process that can also be inhibited by negative regulatory molecules, also known as ‘checkpoint molecules’. The obstruction of these checkpoint molecules such as CTLA4 and PD1 has also shown to have clinical benefit in numerous tumour types.
CTLA4 is a receptor that has an important role in the priming phase of the immune response. PD1 is another inhibitory receptor that obstructs T cell activation and possesses two receptors, PDL1 and PDL2 which are found on immune cells, antigen-presenting cells as well as on tumour cells.
Ipilumab is an antibody that inhibits CTLA4 interactions with its ligands CD80 and CD86 and is approved for the treatment of advanced melanoma. Currently speaking, multiple antibodies that inhibit PD1 or PDL1 are in clinical development with nivolumab and pembrolizumab being two approved for advanced melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) based on trials that demonstrated improvements in overall survival.
However, the exact determinants of response to both PD1 and CTAL4 inhibitors are not well understood. Clinical benefit in both is associated with high tumour mutational load, high pretreatment levels of CD8 T cells or high pretreatment levels of PDL1 on tumour cells as well as high pretreatment levels of tumour infiltrating lymphocytes. These associations ultimately suggest agents that increase these factors will combine effectively with checkpoint therapies.
The serine threonine kinase BRAF is mutated in about half of all malignant melanomas and today multiple agents targeting the MAPK pathway have been approved for the treatment of BRAF positive melanoma including two BRAF inhibitors vemurafenib and dabrafenib.
Phase II and III trials have shown response rates of approximately 50% with significant improvements in progression-free survival and overall survival compared with standard-of-care chemotherapy.
There has unfortunately been some level of resistance to these drugs, suggesting that resistant tumours are dependent on the MAPK pathway for survival. Combining MAPK and BRAF inhibitor therapies has shown improvements in progression-free survival over single agent BRAF inhibitors – though resistance still remains a problem.
VEGF-A is a protein and validated driver of tumour angiogenesis. Figure 2 shows approved therapeutic agents targeting VEGF/VEGFR signalling. VEGFR signalling has the potential to lead to inhibition of T cell infiltration into tumours. Additionally it is associated with reduced dendritic cell differentiation and activation, which may impair T cell priming. In this way inhibition of VEGF/VEGFR signalling can improve intratumoral immune cell infiltration and anti-tumour responses.
Challenges and Considerations
One of the major challenges for combining targeted therapies and immunotherapies is the potential for combined toxicity. The irony of the situation is that while concurrent therapies may offer the greatest potential for synergistic response, they also present the greatest risk of toxicity with sequential treatments. The issue has been found in earlier trials involving the combined treatment of vemurafenib and ipilimumab which was subsequently terminated for this reason. To date, most toxicities observed with combination therapy has been reversible or addressed through drug holidays, changes in dose levels or through the administration of steroids.
Other important considerations for the development and progression of combination therapies are optimizing dose regimens and selecting appropriate endpoints in assessing efficacy. Most trials monitor any significant reductions in tumour size using a radiographic assessment and is considered a positive response under the Response Evaluation Criteria in Solid Tumours (RECIST). The downside of RECIST is that there a small but significant number of patients who have mixed or delayed clinical response, with some exhibiting an initial increase in the size of their lesions which was then followed by reductions in tumour volume. It is therefore necessary to understand and take on board the complexities of immune-related responses and thereby potentially modify strict criteria for clinical benefit.
To the Future
The discovery of important molecular pathways that promote cancer growth and the development of drugs that specifically inhibit these pathways has led to an ushering in of a new era of cancer medicine. The combination of immunotherapy with targeted therapy has clearly demonstrated great potential as a new cancer treatment strategy, however further tweaking and optimisation is still needed.
Aside from the MAPK and VEGF pathways, other combinations are still being assessed in the laboratory and of particular note are EGFR and ALK inhibitors combined with checkpoint inhibitors in NSCLC. The outcomes of these trials will provide further insights into the full potential of such treatments as well as the ability of targeted therapies to prime the environment of the tumour for response to immunotherapy.
Additionally, the role of radiation therapy and chemotherapy in complementing checkpoint inhibitors by enhancing aspects of cancer immunity are still being examined. In this way we can see that there are now and will be a vast array of options for cancer patients all of which possess the ability to significantly improve outcomes in progression-free and overall survival compared with current standard-of-care.