Dinoprostone

A new study has discovered how a lipid molecule found at high levels within tumors undermines the anti-cancer immune response and compromises a recently approved immunotherapy known as adoptive cell therapy (ACT) using tumor infiltrating lymphocytes, or TIL-ACT. A Ludwig Cancer Research study has discovered how a lipid molecule found at high levels within tumors undermines the anti-cancer immune response and compromises a recently approved immunotherapy known as adoptive cell therapy (ACT) using tumor infiltrating lymphocytes, or TIL-ACT. In this individualized cell therapy, TILs -- CD8+ T cells that kill cancer cells -- are expanded in culture from a patient's tumor samples and reinfused into the patient as a treatment. Researchers led by Ludwig Lausanne's Matteo Morotti, Alizee Grimm, Denarda Dangaj Laniti and Director George Coukos report in the current issue of Nature their discovery -- based on analyses of data and samples collected in TIL-ACT clinical trials -- of the mechanism by which the lipid, prostaglandin E2 (PGE2), poisons TIL metabolism to serve as a checkpoint against their anti-tumor activity. They also show that disrupting that mechanism during the cell culture processes employed in TIL-ACT dramatically improves the therapeutic potential of transferred TILs in mouse models of cancer. A companion study led by researchers at the Technical University of Munich, done using mouse models of cancer, confirms the Ludwig Lausanne team's findings and appears in the same issue of Nature. Several researchers share authorship of both papers. "These findings have important implications for cancer immunotherapy in general, as they identify a novel and eminently targetable checkpoint against the function of infiltrating cytotoxic T cells in the tumor microenvironment," said Coukos. "More immediately, we can now complete the circle here at Lausanne: we have harnessed the data and materials obtained from TIL-ACT trials in humans to advance our understanding of tumor immunology and can now apply what we have learned to improve outcomes for patients undergoing such therapies. This is a key element of our strategy -- and of Ludwig's overall mission." The Ludwig Lausanne researchers began by examining gene expression data collected from T cells isolated from patients for TIL-ACT. Their analysis revealed that the TILs that already bore markers of response to interleukin-2 (IL-2) -- a factor essential to functional vitality and proliferation of T cells -- were the ones that expanded best in culture. The researchers also tracked the growth in culture of 215 individual tumor-reactive TILs that respond to IL-2, which is a key component of TIL cultures, and showed that this is indeed the case. Further examination of gene expression data collected from clinical trial samples revealed that TILs that responded poorly to IL-2 expressed relatively large numbers of receptors for PGE2 on their surfaces. In line with that finding, anti-cancer TILs from tumor fragments that had high levels of PGE2 were found to expand poorly in culture. To explore how PGE2 compromises TIL-ACT, the researchers began by identifying a signature of gene expression associated with PGE2's effects on T cells. "We found that patients' tumor-reactive TILs that bore this PGE2 signature expanded very poorly in culture, and that these TILs were often in states that would otherwise be essential to therapeutic responses," said Morotti. "Further, corresponding clinical trial data revealed that the melanoma patients whose TILs bore that signature had responded poorly to TIL-ACT therapy." The researchers next probed how PGE2 exerts its effects on TILs. They found that the lipid, acting through its receptors (EP2 and EP4), disrupts the ability of T cells to sense and respond to IL-2 by monkeywrenching the assembly of the IL-2 receptor's component proteins. The resulting loss of IL-2 stimulation initiates a cascade of biochemical events in the cells that culminates in profound metabolic dysfunction, inducing a functional lethargy in the TILs known as "anergy" and ultimately triggering ferroptosis, a type of programmed cell death. The researchers also examined whether blocking PGE2 could overcome these effects. "By adding a drug that inhibits PGE2 production to the TIL culture medium we restored the ability of TILs to respond to IL-2 and improved the expansion of tumor-reactive TILs more than two-fold," said Grimm. "Small molecules that block PGE2 interaction with its receptors had a similar effect. These studies not only confirmed our hypothesis but also identify a means to swiftly translate our findings for clinical application." The researchers show that, grown in the presence of PGE2 inhibitor, tumor-reactive TILs become responsive to IL-2 once again and show signs of renewed metabolic fitness and functional vitality. These TILs prevented cancer cells taken from the tumors they previously inhabited from forming new tumors in mice, while the same TILs grown sans PGE2-inhibitor did not. The revitalized TILs were also better agents of TIL-ACT therapy in a mouse model. The companion study in Nature, led by the Jan Böttcher lab in Munich, confirms the findings of this study in mouse models of cancer. It also shows that the inhibition of IL-2 signaling in TILs occurs within the microenvironment of tumors. Engagement of the PD-1 checkpoint on T cells, which is currently targeted by several immunotherapies, is by contrast thought to occur mainly in the lymph nodes around tumors. "When we learned we were working on essentially the same problem, we decided to combine our efforts and publish our shared discoveries as back-to-back publications in the same journal," said Dangaj Laniti. "That spirit of cooperation, rather than the usual, fierce competition, has borne fruit in the discovery of a previously unknown immune checkpoint in tumors that is mechanistically distinct from the PD-1 checkpoint that cancers exploit to foil anti-tumor T cells. It has been very gratifying to be a part of this partnership, whose discoveries will surely be of great benefit to cancer patients." In addition to their posts at Ludwig Lausanne, George Coukos directs the Department of Oncology at the Lausanne University Hospital (UNIL CHUV) and codirects the Swiss Cancer Center Léman and Denarda Dangaj Laniti is the Head of the Tumor Microenvironment and Biomarker Discovery Lab at Ludwig Lausanne. This study was supported by Ludwig Cancer Research, Swiss Cancer League Foundation, the German Research Foundation and grants from the Biltema Foundation, Paul Matson Foundation and Cancera Foundation.

The patient is taking part in a phase 1/2a trial with the immunotherapy drug HTL0039732 for advanced solid tumors. Sosei Heptares’ drug works by blocking signalling through a specific type of prostaglandin receptor – the E2 (PGE2)-type prostanoid receptor 4 (EP4). Sosei Group Corporation, the world-leader in GPCR-focused structure-based drug design (SBDD) and development, and Cancer Research UK, the world’s largest independent funder of cancer research have been working together on the trial evaluating Sosei Heptares’ orally available small molecule cancer immunotherapy drug HTL0039732 for advanced solid tumors. HTL0039732 works by blocking signalling through a specific type of prostaglandin receptor, the prostaglandin E2 (PGE2)-type prostanoid receptor 4 (EP4). In cancer, PGE2 acts in the tumor microenvironment to trigger cancer cells to evade the immune system. Targeting EP4 to block the effects of PGE2 increases the ability of the immune system to detect and control cancer cells and makes HTL0039732 a potential candidate to treat patients with cancers that generally do not respond well to current immunotherapies. Cancers not responding to current immunotherapies These include microsatellite stable colorectal, gastroesophageal, head and neck, and castrate-resistant prostate cancer. Positive results from the trial will bring effective treatment closer to these underserved patient populations. Approximately 80–85% of colorectal cancer patients are classified as ‘microsatellite stable’ (MSS), which means they have low instability in short, repeated sequences of DNA in their tumours, known as microsatellites. MSS tumours often exist in an environment that suppresses the immune system and do not respond well to immunotherapies. googletag.cmd.push(function () { googletag.display('text-ad1'); }); Matt Barnes, president of Heptares Therapeutics and head of UK R&D, said: “We are very pleased to be collaborating with Cancer Research UK to advance HTL0039732 into clinical development. This novel oral small molecule drug candidate was rationally designed using our SBDD platform and has the potential to become a best-in-class approach to enhance the efficacy of immunotherapies used to treat many cancer patients.” Cancer Research UK’s Centre for Drug Development (CDD) is sponsoring, designing and conducting the trial with three main objectives: to define the toxicity, tolerability and pharmacokinetics of HTL0039732, to identify the recommended dose for phase 2 studies, and to assess its antitumor activity as a monotherapy and in combination with the PD-L1 inhibitor atezolizumab. 'Desperately need more trials like this' Nigel Blackburn, director of Cancer Research UK’s CDD, said: “We are delighted to have reached this next significant milestone in our partnership with Sosei Heptares. The fact that immunotherapy works for some patients but not others means we desperately need more trials like this to open up potentially life-saving treatment options to more people.” Phase 2a of the trial will expand the optimal combination dose in up to four cohorts in specified cancer indications. Sosei Heptares holds a license to the results generated under the trial to continue the clinical development and commercialization of HTL0039732. Chief investigator Bristi Basu, University of Cambridge, and co-chief investigator Debashis Sarker, King’s College London, are leading the trial. Patient recruitment has been initiated in the UK at Cambridge University Hospitals and Guy’s and St Thomas’ NHS Foundation Trusts, with additional sites across the Experimental Cancer Medicine Centre (ECMC) network to open soon. Immnosuppresive environment Dr. Bristi Basu, University of Cambridge, said: “We are excited to be opening a new UK clinical trial using HTL0039732 to target a protein called EP4, a member of the prostaglandin receptor family that has been implicated in creating the immunosuppressive environment which promotes tumor growth in multiple cancer types. “By studying HTL0039732 alone and in combination with immunotherapy, we aim to understand more about how to optimize modulation of the immune system to fight cancers. We hope that this EP4-targeting approach will deliver a promising route to improving treatment options for patients with a broad range of cancers.” The UK Medicines and Healthcare products Regulatory Agency (MHRA) has granted HTL0039732 an Innovation Passport, the first step in its Innovative and Licensing Access Pathway (ILAP), which aims to improve patient access to new medicines by reducing the time to market. The MHRA grants Innovation Passports to medicines that treat life-threatening or seriously debilitating conditions, and where there is a significant patient or public health need.