the use of fresh versus archived material and whether the primary tumour and/or ... special passion of hers. Email: anne
Watch Pages Advances in Immunotherapy – A Perspective from ASCO 2015 Novel immunotherapy approaches have revolutionised the treatment of certain cancers in recent years. Since the first results from checkpoint inhibitor therapy were published, we have gained further understanding of the underlying mechanisms and the potential of immunotherapy. ASCO 2015 had several sessions dedicated to this exciting and rapidly expanding field. There are currently nearly 280 studies with checkpoint inhibitors ongoing globally across a span of tumour types. Most of these involve PD1 inhibitors or PD-L1 inhibitors, or a combination of these with the oldest member of the checkpoint inhibitor family, ipilimumab. It has been established that there is likely a correlation between the mutational load of the tumour and the efficacy of checkpoint inhibitors. This aspect was elegantly investigated in a study with pembrolizumab monotherapy that looked at colon cancer with microsatellite instability. As postulated, the mismatch repair deficient cohort with high mutational load had a good response rate at around 60 per cent. The mismatch repair proficient colon cancer group, in sharp contrast, had a 0 per cent response rate. 1
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So to make treatment with checkpoint inhibitors effective, the tumour ideally needs to offer a high number of suitable neo-antigens that the T-cells can target. However, even in tumours with high mutational load, not all patients respond equally well. The search for predictive biomarkers to potentially select patients who will benefit from checkpoint inhibitor therapy is another very important area of research. Several studies suggest that high expression of PD-L1 in the tumour tissue correlates with positive response to PD1 (or PDL1) inhibitors. In NSCLC studies, for example, response rate in subgroups with high PD-L1 expression was nearly twice as high as the overall response rate for all patients. PD-L1 expression is however not yet ready for use as a predictive biomarker, due to inconsistencies in the assays used; thresholds used to define the analysis populations; the use of fresh versus archived material and whether the primary tumour and/or metastatic tumour tissue should be targeted for analysis. Moreover, it is important to note that also some patients in the PD-L1 negative group do show responses. The value of the PD-L1 marker may therefore not be to exclude certain patients from checkpoint inhibitor therapy, but rather to define a
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Watch Pages Other combination treatments may also have their value. Vaccines, PAMPs (pathogen-associated molecular patterns) or toll-like receptor agonists may all work well in combination with checkpoint inhibitors, and may have preferable safety profiles than the ipilimumab combination. Adoptive cellular therapy such as CAR T-cells is an entirely different approach to immunotherapy. This treatment strategy has been incredibly successful in certain liquid tumours, and initial studies in solid tumours were reported at ASCO. Observed efficacy in Phase I pancreatic cancer and glioblastoma studies is however by far less impressive than seen previously with anti CD19 CAR T-cells in liquid cancers. In the solid tumour setting, efficacy of CAR T-cell treatment may be limited by finding an appropriate target antigen, but also by immunosuppressive mechanisms in the tumour tissue. A combination with checkpoint inhibitors might be a valuable solution for this latter problem. Finally, a limiting factor for CAR T-cell therapy is the laborious process of T-cell extraction, engineering and expansion, which currently cannot be performed everywhere in clinical practice. To address this issue, work is underway to look into allogeneic “off-the-shelf” adoptive T-cell immunotherapy using engineered cells from healthy donors. subset of patients where monotherapy is highly likely to be successful, whereas for other patients a combination therapy should be considered. The presence of PD-L1 in the tumour tissue, which is correlated with better response to PD1/PD-L1 inhibitors, suggests that the tumour is already fighting against immune attack, i.e. tumour specific T-cells have, in principle, infiltrated the tumour. In this scenario, it is sufficient to release the PD1 mediated blockage to elicit an efficient immune response. In patients where the initial T-cell infiltration has not yet occurred, however, PD1 or PD-L1 inhibitor therapy will not be effective, and has to be complemented with other drugs to initiate the process. One option is to add ipilimumab, which targets the earlier step of T-cell induction in lymphoid organs prior to the cells being released into the periphery. Indeed, combination trials show better response rates than monotherapy with either of the drugs. Several important studies are ongoing, for which results are eagerly awaited. The combination of ipilimumab and PD1 or PD-L1 inhibitors shows significantly higher toxicity than PD1/ PD-L1 inhibitor alone. The side-effects observed are within the expected range of immunologic toxicities and can generally be managed by immunosuppressive therapy (mostly steroid treatment). Importantly, immunosuppression for management of immunologic side-effects does not have a negative influence on treatment outcome, as evidenced by subgroup analysis of patients who received steroid treatment. www.jforcs.com
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In summary, the immunotherapy area remains as dynamic and exciting as always, yet there are still many open questions. Until we are in a position to define the optimal treatment regimen for each patient, it will remain important to take into account the appropriate predictive biomarkers for determining which patients should be selected to receive monotherapy versus different possible combination treatments. However, we now have a number of tools in hand that show promising results and deserve to be further explored for discovering the best sequence or combination of therapies in various cancer types. References 1 D. T. Le et al., oral abstract presentation LBA 100 at 2015 ASCO (American Society of Clinical Oncology) Annual Meeting.
Anne Gromöller, Ph.D., Senior Project Director, Oncology, provides project oversight for clinical studies conducted by INC Research. Her background is in biochemistry, and she has work experience in both pharmaceutical and CRO environments. Anne focuses on the solid tumour segment within INC Research’s Oncology Business Unit, and immunotherapy approaches are a special passion of hers. Email:
[email protected]. Website: www.incresearch.com. Journal for Clinical Studies 11
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