Benefit Of Cancer Immunotherapy Research Articles

Heterogeneity of Cancer-Associated Fibroblasts and the Tumor Immune Microenvironment in Pancreatic Cancer.

Simple SummaryStroma-targeting therapy in pancreatic ductal adenocarcinoma (PDAC) has been extensively investigated, but no candidates have shown efficacy at the clinical trial stage. Studies of cancer-associated fibroblast (CAF) depletion in a mouse model suggested that CAFs have not only tumor-promoting function but also tumor-suppressive activity. Recently, single-cell RNA sequencing (scRNA-seq) has revealed the complex tumor microenvironment within PDAC, and subpopulations of functionally distinct CAFs and their association with tumor immunity have been reported. However, the existence of tumor suppressive CAFs and CAFs involved in the maintenance of PDAC differentiation has also been reported. In the future, therapeutic strategies should be developed considering these CAF subpopulations, with the hope of improving the prognosis of PDAC.Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a 5-year survival rate of 9%. Cancer-associated fibroblasts (CAFs) have historically been considered tumor-promoting. However, multiple studies reporting that suppression of CAFs in PDAC mouse models resulted in more aggressive tumors and worse prognosis have suggested the existence of a tumor-suppressive population within CAFs, leading to further research on heterogeneity within CAFs. In recent years, the benefits of cancer immunotherapy have been reported in various carcinomas. Unfortunately, the efficacy of immunotherapies in PDAC has been limited, and the CAF-driven cancer immunosuppressive microenvironment has been suggested as the cause. Thus, clarification of heterogeneity within the tumor microenvironment, including CAFs and tumor immunity, is urgently needed to establish effective therapeutic strategies for PDAC. In this review, we report the latest findings on the heterogeneity of CAFs and the functions of each major CAF subtype, which have been revealed by single-cell RNA sequencing in recent years. We also describe reports of tumor-suppressive CAF subtypes and the existence of CAFs that maintain a differentiated PDAC phenotype and review the potential for targeted therapy.

Innate myeloid cells in the tumor microenvironment.

Cancer immunotherapies are receiving increasing approval in the clinic, but still only a fraction of patients benefit long-term. Understanding the most important mechanisms of immunotherapeutic resistance is critical for broader utility and benefit of cancer immunotherapy. While the tumor microenvironment (TME) is made up of many cell types, immunosuppressive monocytes/macrophages, granulocytes and myeloid derived suppressor cells interact with, and play a critical role in regulating the anti-tumor lymphocyte effector cells that mediate effective immunotherapies. Herein, we discuss the latest research that has identified and compared the importance of pro-tumor and immunosuppressive mechanisms that tumor infiltrating myeloid cells employ. Exploiting this new information may help to develop totally novel therapies to boost contemporary cancer immunotherapy.

Abstract 2273: Selection of first-in-human clinical dose range for the tumor-targeted 4-1BB agonist MP0310 (AMG 506) using a pharmacokinetic/pharmacodynamics modeling approach

Abstract Following the clinical success of checkpoint inhibitors, cancer immunotherapy is rapidly expanding into combination treatments to enhance response rates and duration. Engagement of co-stimulatory molecules from the tumor necrosis factor receptor (TNFR) superfamily, including 4-1BB, may be a promising approach to enhance the benefits of cancer immunotherapy. Agonistic antibodies against the costimulatory receptor 4-1BB (CD137) have been shown to effectively enhance the anti-tumor activity of checkpoint inhibitors and other agents in preclinical animal models. However, the clinical development of 4-1BB agonistic antibodies has met with limited success thus far. Anti-4-1BB monoclonal antibodies have either been reported to cause significant dose-limiting hepatotoxicity or demonstrated limited efficacy as single agent therapeutics. We generated a DARPin® therapeutic candidate, MP0310 (AMG 506), which comprises domains binding to 4-1BB and fibroblast activation protein (FAP). MP0310 triggers 4-1BB activation only if bound and clustered via FAP which is abundantly expressed by cancer associated fibroblasts present in many solid tumors. In vitro functional assays indicate that MP0310 is a potent T cell co-stimulator in the presence of FAP-expressing cells. In vivo activity of tumor-targeted 4-1BB agonism was assessed in the HT-29 colon carcinoma xenograft model in PBMC humanized mice in combination with a T cell engager. Consistent with tumor targeting, MP0310 enhanced intra-tumoral CD8 T cell expansion while showing only limited systemic activity. We used a translational pharmacokinetic-pharmacodynamic (PK-PD) modeling approach to integrate in vitro and in vivo data to support the estimation of a minimal anticipated biological effect level (MABEL) and the relevant dose range for first in human (FIH) studies. In addition to a PK model describing the MP0310 concentrations over time in mouse and monkey, direct and indirect response models were used to describe receptor occupancy (RO), intra-tumoral CD8 T cell infiltration and peripheral CD8 count kinetics. Predictions from the combined PK and PD models using average intra-tumoral and peripheral drug concentrations (Cav) provide a MABEL dose with minimal expected systemic PD effects at 20% RO as well as the anticipated therapeutic dose range in humans. In conclusion, our PK/PD-modeling approach provides support for the selection of a safe starting dose for MP0310 (AMG506) in patients. It provides a rationale for selecting the maximum tested dose, and may help reduce the number of cancer patients receiving sub-therapeutic doses. MP0310 (AMG 506) is currently being evaluated in a Ph1 clinical study. Citation Format: Alexander Link, Laurent Juglair, Heïdi Poulet, Guy Lemaillet, Christian Reichen, Patricia Schildknecht, Ivana Tosevski, Joanna Robinson, Niina Veitonmäki, Jörg Herbst, Keith Dawson, Christof Zitt, Camila de Almeida, Rik de Greef, Victor Levitsky, Michael T. Stumpp, Hong Ji, Elmar Vom Baur. Selection of first-in-human clinical dose range for the tumor-targeted 4-1BB agonist MP0310 (AMG 506) using a pharmacokinetic/pharmacodynamics modeling approach [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2273.

Abstract 2231: A simple blood base test for predicting clinical benefit of cancer immunotherapy

Abstract Immunotherapy with immune check point inhibitors (CPI) has dramatically transformed cancer therapy. However, only ~25% cancer patients have a positive clinical response to CPI. Moreover, the cost of the treatment and the risk of severe side effects makes it necessary to develop biomarkers to predict the benefit of the treatment. It has been shown that the tumor neoantigen load correlates with a positive response to treatment. This indicates that pre-existing anti-tumor immune responses to neoantigens can be used for the CPI response prediction. We have discovered a new source of frameshift (FS) neoantigens created by errors in RNA production in tumor cells, including the insertion and deletion (INDEL) of microsatellite regions during the RNA transcription and the mis-splicing of exons. These errors can generate FS neoantigens, which are highly immunogenic and can elicit both T cell and B cell immune response in cancer patients. We have shown that, although most antibody reactivity to FS peptides (FSPs) are personal, there are common antibodies reactive in different cancer patients, even across different cancer types. The FSPs with positive reactive antibodies can offer protection in mouse tumor models as vaccines. We thus hypothesize that antibodies reactive to FSPs in cancer patients can be used for predicting the clinical benefit of cancer immunotherapy. There is a total of~ 220,000 potential FS neoantigens that can be generated by INDELs of transcription and mis-splicing of genes. These neoantigens can be represented by ~400,000 FSPs, 15-amino acids peptides. We have created arrays of by in-situ synthesis of these FSPs. We used these array to test our hypothesis with pre-treatment serum of 40 cancer patients, from 26 different cancer types in clinical trials with CPI treatments. A total of 13 patients had a clinical response to CPI treatment. Similar to ELISA, diluted serum were applied to the FSP array, and total IgG were detected by fluorescent labeled antibody. IgG reactive to each FSP was measured by the fluorescent intensity and then median normalized within each array for the analysis. As predicted, there are common IgG antibodies reactive to FSPs in the response patients. By selecting 100 to 500 most significantly different reactive FSPs between two group patients, and trained with prediction models, such as SVM, our FSP array can reach up to 96% accuracy in the prediction of clinical response with leave-one-out validation. We hypothesize that the FSPs with positive IgG reactive in response patients may be related to anti-tumor immune response, which is need to be further investigated. We also showed that the FSP array can potentially predict the patients who may have high grade immune related adverse events with the CPI treatment. Our preliminary data indicates that the FSP array is a promising technology for predicting the clinical benefit of immunotherapy. We will expand our sample size to further evaluate this technology. Citation Format: Luhui Shen, Jianfen Chen, Stephen Albert Johnston, David Hong, Jianjun Gao, Aung Naing. A simple blood base test for predicting clinical benefit of cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2231.

Combinations Therapies.

Immunotherapy of cancer encompasses different strategies that elicit or enhance the immune response against tumors. The first results from clinical studies have provided promising data for the treatment of lung cancer patients with immunomodulating monotherapies. To improve the potential benefit of cancer immunotherapy, synergistic combinations of the various immunotherapy approaches or of different elements within each of the immunotherapy approaches are being explored. The rationale typically involves different but complementary mechanisms of action, eventually impinging on more than one immune system mechanism. As a prominent example, the simultaneous blockade of PD-1 and CTLA-4 is giving rise to therapeutic synergy, while still offering room for efficacy improvement. Moreover, combinations of immunomodulating agents with chemotherapy or targeted molecules are being tested. Animal models suggest that immunotherapies in combination with these various options offer evidence for synergistic effects and are likely to radically change cancer treatment paradigms. However, data obtained so far indicate that toxic side effects are also potentiated, which may even restrict the selection of patients that are suitable for these combinational approaches. Advancing the field of combinatorial immunotherapy will require changes in the way investigational agents are clinically developed as well as novel experimental end-points for efficacy evaluation. However, this combined therapeutic manipulation of both tumor and stromal cells may lead to a dramatic change in the therapeutic options of lung cancer patients in any disease stage that can only grossly be appreciated by the current studies.

Developing cancer immunotherapies

AbstractEffective antitumor responses require communication between antigen‐presenting cells, T‐cell subsets, B cells and natural killer cells. However, tumors have developed a number of mechanisms to avoid detection and elimination by the immune system. This results in a microenvironment that can contribute to the failure of the immune response to the tumor or the prevention of effective immune‐mediated killing. Understanding the barriers to effective tumor immunity allows for the rational design of targeted immunotherapies. The characterization of tumor antigens has led to the development of promising vaccine candidates. Our work has concentrated on the cancer/testis antigen NY‐ESO‐1, which has been an important focus in the development of vaccine‐based therapies against melanoma. Immune responses against NY‐ESO‐1 can occur spontaneously or be induced by vaccination in patients with resected disease. In contrast, the use of NY‐ESO‐1 vaccines in the advanced melanoma setting has been disappointing, with reduced clinical and immunological efficacy. This lack of response is observed in other disease settings with other antigens, and might in part be explained by the recruitment of increased numbers of T‐regulatory cells and a strong immunosuppressive environment. The benefits of cancer immunotherapy might be enhanced if it were possible to identify characteristics that distinguish patients who are more likely to respond.