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Enjoy reading! - The SMS-oncology team
Chicago hosted the 2018 annual meeting of the American Association for Cancer Research (AACR) in its cold spring days. As expected, enthusiasm centered on immunotherapy combination therapy and its challenges, and the possibilities offered by precision medicine. Emerging biomarkers, circulating tumor cells / DNA and liquid biopsy methodologies, as well as utilization of artificial intelligence (AI) in anti-tumor response prediction were featured in many parallel sessions.
With more than 8,000 of cancer immunotherapy trials ongoing, a large amount of presentations focused on checkpoint inhibitors (CPi) and combinations with other immune-oncology (IO) agents, targeted therapies and chemotherapies. While FDA and EMA approvals have extended the use of CPis across several cancer types and indications (Table 1) large population of patients remains non-responding to current CP blockade therapies urging investigations to go beyond CTLA-4 and PD1 / PD-L1.
Table 1: Approved checkpoint inhibitors by FDA and EMA
*Only in Japan and South Korea
Next generation immune checkpoint inhibitors and new target pathways being explored as an opportunity to overcome the challenges of current CPi therapies, were highlighted in the opening plenary session by Padmanee Sharma (MD Anderson Cancer Center, Houston, USA) and Ana Anderson (Harvard Medical School / Brigham & Woman’s Hospital, Boston, USA). Lymphocyte activation gene-3 LAG3 (CD223) with its high affinity to MHCII; TIM-3 and TIGIT inhibitors are receiving growing interest due to their synergistic effect in combinations with anti-PD1 molecules (Figure 1). OX-40, GITR and CD137 are new generation positive immune modulators shown to be effective in combination with adoptive cell therapy. Studies with CD137 agonists have shown to extend the engagement of T cells with the target.
Figure 1: Next generation checkpoint inhibitors and effective pathways
(Adapted from Ana Anderson AACR18 – The next generation of checkpoint inhibitors)
Alternative pathways to target the immune system were also discussed (Figure 2). Out of many, two T cell co-stimulatory molecules were specifically highlighted: ICOS and CD40. Agonists of ICOS (inducible T cell co-stimulator) and CD40 (antigen presenting cell maturation co-factor) were found to generate optimal anti-tumor responses in combination with anti-CTLA4 therapy. Analysis of post CPi treatment tumor biopsy of non-responding patients has revealed novel inhibitory pathway molecules such as VISTA and CD47 as potential targets in IO resistant setting.
Figure 2: Opportunities beyond checkpoint inhibitors
(Ab: antibody; CP: Check-point. Adapted from Vonderheide et. al Clinical Cancer Research 2017)
Another reinvented approach presented was the engagement of the innate immune system through oncolytic viruses. Agonists of Pattern Recognition Receptors (PRR) such as Toll-Like Receptors (TLRs) may provide an avenue for overcoming resistance to CPis. Investigators from the Centre Léon Bérard in Lyon (France) studied commercially available vaccines based on attenuated rotavirus, in pre-clinical immunocompetent mouse models. After confirming that the vaccines have PRR agonist properties, it was also demonstrated that rotaviruses have oncolytic properties. Intra-tumoral administration of such vaccines overcame resistance to CPis and showed synergistic anti-tumor activity in combination with anti-CTLA4 treatment. Similarly, induction of TLR pathway via Newcastle Disease Virus (NDV) has been shown to increase T cell infiltration not only on the local injection site but also in the distant tumors. Studies are ongoing to test combination of NDV plus CTLA4-i to increase clinical activity. At the clinical end, investigators from Leeds Institute of Cancer and Pathology (Leeds, UK) showed in a recent Phase I pilot study that intravenous (IV) delivery of reovirus to patients with high-grade glioma or brain metastases resulted in increased T cell infiltration into tumors.
Several presenters discussed development in CAR-T cell therapy including the efforts to develop off-the-shelf approaches by several biotechnology companies. Technical aspects related to manufacturing processes and quality control are gradually improving but there is still some way to go. On the clinical side, several developments were also reported. In a late-breaking presentation, researches from the University of Pennsylvania (Philadelphia, USA) described how they used multiple CAR-T variants in combination with CPis and found that they induced selective cell killing in GBM models. More specifically, IL13Rα2-targeting CAR-T cells greater anti-tumor effect when paired with anti-CTLA4 treatment, while EGFRvIII-targeting CAR-T cells had the largest effect when paired with anti-PD-1 treatment; indicating that a more personalized approach may be needed. In addition, the researchers also concluded that development of a broad portfolio of both selective and promiscuous CAR-T constructs targeting the various forms of EGFR is likely to provide coverage over a larger proportion of both, GBM tumor volume and regionally-specific tumor cells.
Biomarkers and their growingly inseparable role in cancer therapy also dominated the AACR2018 talks and the posters. Rational biomarker selection is seen as the key to unveil the full potential of IO (Figure 3). One of the main challenges for the use of biomarkers is setting the threshold for positivity. Inconsistency in different threshold measures emerge from factors such as heterogeneity of the tumors, comparison of different drugs targeting the same pathways as well as the temporal differences and technical and validation aspects of the particular assays used. Several presenters in plenary sessions reviewed the studies assessing PD-L1 and its predictive value in therapy involving CPis. Most agreed that, even though this may be questionable, PD-L1 should continue to be assessed as it allows understanding and exploration of disease biology and evolution.
Meanwhile increasing emphasis is now placed on tumor mutational burden (TMB) which was referred to as having the potential to be “a pan-cancer biomarker”. Data from the nivolumab in combination with ipilimumab CheckMate 568 clinical trial, in first line non-small cell lung cancer (NSCLC), showed that tumor response correlated with a TMB rate of up to 10 mutations/ Mb and reached a plateau at 15 mutations/ Mb. When moving TBM assays into the clinic, the same issues regarding definition and variability of low and high threshold arise. Standardization of assays and optimizing the results for individual tumor phenotypes should be undertaken as preventive measures for inconsistencies. Alongside TMB, the use of neoantigens and prediction of the most immunoreactive neoeptiopes, as well as the patient its HLA genotype and clonality are major concepts being explored pre-clinically and in clinical trials. Advances in neoantigen identification has already led to several early stage clinical studies using neoantigen vaccines where they have been shown to generate and enhance T cell responses. Thus offering intriguing possibilities for combination therapy with CPis.
Figure 3: Biomarkers for anti-cancer immunotherapy
CTC: Circulating Tumor Cells, ctDNA: circulating tumor DNA, IHC: Immunohistochemistry
The breakthroughs of immunotherapy combinations trials are likely to generate for welcoming dilemmas for physicians treating patients with NSCLC. Updated data from KEYNOTE-189, CheckMate 227 and IMpower150 were in the same plenary session, with the former two studies also being simultaneously based in the New England Journal of Medicine on the same day. It has already been possible for patients with non-squamous NSCLC to receive pembrolizumab together with pemetrexed and a platinum-based drug in first line therapy. They may also soon have the option to have atezolizumab in combination with bevacizumab plus carboplatin and paclitaxel. In CheckMate 227, in patients with untreated stage IV or recurrent NSCLC (squamous or non-squamous) who have a high TMB, Progression Free Survival (PFS) was significantly longer with nivolumab plus ipilimumab than with chemotherapy, irrespective of PD-L1 expression level.
There is no question that immunotherapy is now an established modality in anti-cancer treatment. Combinations involving different immunotherapy products or with other modalities (e.g. chemotherapy or targeted therapy) are set to further improve clinical outcomes. So what is next? Judging by the attention received at this year’s AACR, even more immunotherapies; in the form of small molecules and antibodies targeting novel IO targets or complex cellular therapies involving engineered immune cells, oncolytic viruses and neoantigen-based vaccines are emerging to the spot-light.
Nadina Grosios PhD MPH, Director Consultancy
Yuva Oz MSc, Business Developer