Challenges and Future Perspectives of Immunotherapy in Pancreatic Cancer

To date, extensive efforts to harness immunotherapeutic strategies for the treatment of pancreatic ductal adenocarcinoma (PDAC) have yielded disappointing results in clinical trials. These strategies mainly focused on cancer vaccines and immune checkpoint inhibitors alone or in combination with chemotherapeutic or targeted agents. However, the growing preclinical and clinical data sets from these efforts have established valuable insights into the immunological characteristics of PDAC biology. Most notable are the immunosuppressive role of the tumour microenvironment (TME) and PDAC’s characteristically poor immunogenicity resulting from tumour intrinsic features. Moreover, PDAC tumour heterogeneity has been increasingly well characterized and may additionally limit a “one-fits-all” immunotherapeutic strategy. In this review, we first outline mechanisms of immunosuppression and immune evasion in PDAC. Secondly, we summarize recently published data on preclinical and clinical efforts to establish immunotherapeutic strategies for the treatment of PDAC including diverse combinatorial treatment approaches aiming at overcoming this resistance towards immunotherapeutic strategies. Particularly, these combinatorial treatment approaches seek to concomitantly increase PDAC antigenicity, boost PDAC directed T-cell responses, and impair the immunosuppressive character of the TME in order to allow immunotherapeutic agents to unleash their full potential. Eventually, the thorough understanding of the currently available data on immunotherapeutic treatment strategies of PDAC will enable researchers and clinicians to develop improved treatment regimens and to design innovative clinical trials to overcome the pronounced immunosuppression of PDAC.

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Immunmodulatory Treatment Strategies of Hepatocellular Carcinoma: From Checkpoint Inhibitors Now to an Integrated Approach in the Future

Cancers ◽

10.3390/cancers13071558 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1558

Author(s):

Matthias Ocker ◽

Christian Mayr ◽

Tobias Kiesslich ◽

Sebastian Stintzing ◽

Daniel Neureiter

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Trials ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Treatment Strategies ◽

Human Tumor ◽

Standard Of Care ◽

Immune Checkpoints ◽

Published Data ◽

Ablative Techniques

Background: Hepatocellular carcinoma (HCC) still represents a human tumor entity with very limited therapeutic options, especially for advanced stages. Here, immune checkpoint modulating drugs alone or in combination with local ablative techniques could open a new and attractive therapeutic “door” to improve outcome and response rate for patients with HCC. Methods: Published data on HCC experimental to pre-(clinical) treatment strategies from standard of care to novel immunomodulatory concepts were summarized and discussed in detail. Results: Overall, our knowledge of the role of immune checkpoints in HCC is dramatically increased in the last years. Experimental and pre-clinical findings could be translated to phase 1 and 2 clinical trials and became standard of care. Local ablative techniques of HCC could improve the effectivity of immune checkpoint inhibitors in situ. Conclusions: This review demonstrates the importance of immunomodulatory treatment strategies of HCC, whereby the “best treatment code” of immune checkpoint drugs, combination with ablative techniques and of timing must be evaluated in coming clinical trials.

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Stromal biology and therapy in pancreatic cancer: ready for clinical translation?

Gut ◽

10.1136/gutjnl-2018-316451 ◽

2018 ◽

Vol 68 (1) ◽

pp. 159-171 ◽

Cited By ~ 76

Author(s):

Albrecht Neesse ◽

Christian Alexander Bauer ◽

Daniel Öhlund ◽

Matthias Lauth ◽

Malte Buchholz ◽

...

Keyword(s):

Tumour Progression ◽

Treatment Strategies ◽

Dynamic Network ◽

Tumour Microenvironment ◽

Scientific Activity ◽

Ductal Adenocarcinoma ◽

Therapeutic Resistance ◽

Network Systems ◽

Extracellular Matrix Components ◽

Niche Formation

Pancreatic ductal adenocarcinoma (PDA) is notoriously aggressive and hard to treat. The tumour microenvironment (TME) in PDA is highly dynamic and has been found to promote tumour progression, metastasis niche formation and therapeutic resistance. Intensive research of recent years has revealed an incredible heterogeneity and complexity of the different components of the TME, including cancer-associated fibroblasts, immune cells, extracellular matrix components, tumour vessels and nerves. It has been hypothesised that paracrine interactions between neoplastic epithelial cells and TME compartments may result in either tumour-promoting or tumour-restraining consequences. A better preclinical understanding of such complex and dynamic network systems is required to develop more powerful treatment strategies for patients. Scientific activity and the number of compelling findings has virtually exploded during recent years. Here, we provide an update of the most recent findings in this area and discuss their translational and clinical implications for basic scientists and clinicians alike.

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Novel Therapies for Relapsed and Refractory Neuroblastoma

Children ◽

10.3390/children5110148 ◽

2018 ◽

Vol 5 (11) ◽

pp. 148 ◽

Cited By ~ 11

Author(s):

Peter Zage

Keyword(s):

Clinical Trials ◽

Treatment Strategies ◽

Current Treatment ◽

Disease Relapse ◽

Therapeutic Modalities ◽

Treatment Regimens ◽

Novel Treatment ◽

Improved Outcomes ◽

Outcomes For Children ◽

Novel Treatment Strategies

While recent increases in our understanding of the biology of neuroblastoma have allowed for more precise risk stratification and improved outcomes for many patients, children with high-risk neuroblastoma continue to suffer from frequent disease relapse, and despite recent advances in our understanding of neuroblastoma pathogenesis, the outcomes for children with relapsed neuroblastoma remain poor. These children with relapsed neuroblastoma, therefore, continue to need novel treatment strategies based on a better understanding of neuroblastoma biology to improve outcomes. The discovery of new tumor targets and the development of novel antibody- and cell-mediated immunotherapy agents have led to a large number of clinical trials for children with relapsed neuroblastoma, and additional clinical trials using molecular and genetic tumor profiling to target tumor-specific aberrations are ongoing. Combinations of these new therapeutic modalities with current treatment regimens will likely be needed to improve the outcomes of children with relapsed and refractory neuroblastoma.

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Immunotherapy for Glioma: From Illusion to Realistic Prospects?

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2014.34.51 ◽

2014 ◽

pp. 51-59 ◽

Cited By ~ 1

Author(s):

Pierre-Yves Dietrich ◽

Valérie Dutoit ◽

Paul R. Walker

Keyword(s):

Clinical Trials ◽

T Cell ◽

Checkpoint Inhibitors ◽

Treatment Strategies ◽

Cell Receptor ◽

High Avidity ◽

Antigen Receptors ◽

T Cell Therapy ◽

Preferential Expression

There is now evidence that the rules established for tumor immunology and immunotherapy in general are relevant for brain tumors. Treatment strategies explored have mainly involved vaccines using either tumor cells or components, and vaccines with defined synthetic peptides. This latter approach offers the advantage to select well-characterized antigens with selective or preferential expression on glioma. This is a prerequisite because collateral damage to the brain is not allowed. A second strategy which is reaching clinical trials is T cell therapy using the patients' own lymphocytes engineered to become tumor reactive. Tumor specificity can be conferred by forced expression of either a high-avidity T cell receptor or an antitumor antibody (the latter cells are called chimeric antigen receptors). An advantage of T cell engineering is the possibility to modify the cells to augment cellular activation, in vivo persistence and resistance to the tumor immunosuppressive milieu. A direct targeting of the hostile glioma microenvironment will additionally be required for achieving potent immunotherapy and various trials are assessing this issue. Finally, combining immunotherapy with immune checkpoint inhibitors and chemotherapy must be explored within rigorous clinical trials that favor constant interactions between the bench and bedside. Regarding immunotherapy for glioma patients, what was an unrealistic dream a decade ago is today a credible prospect.

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Immunological combination treatment holds the key to improving survival in pancreatic cancer

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-020-03332-5 ◽

2020 ◽

Vol 146 (11) ◽

pp. 2897-2911 ◽

Cited By ~ 2

Author(s):

M. H. Sodergren ◽

N. Mangal ◽

H. Wasan ◽

A. Sadanandam ◽

V. P. Balachandran ◽

...

Keyword(s):

Pancreatic Cancer ◽

Clinical Trials ◽

Checkpoint Inhibitors ◽

Synergistic Effects ◽

Poor Response ◽

Tumour Microenvironment ◽

Combination Treatments ◽

Operative Care ◽

Treatment Responses ◽

Chemotherapy Agents

Abstract Advances in surgery, peri-operative care and systemic chemotherapy have not significantly improved the prognosis of pancreatic cancer for several decades. Early clinical trials of immunotherapy have yielded disappointing results proposing other means by which the tumour microenvironment serves to decrease the immune response. Additionally, the emergence of various subtypes of pancreatic cancer has emerged as a factor for treatment responses with immunogenic subtypes carrying a better prognosis. Herein we discuss the reasons for the poor response to checkpoint inhibitors and outline a rationale why combination treatments are likely to be most effective. We review the therapies which could provide optimal synergistic effects to immunotherapy including chemotherapy, agents targeting the stroma, co-stimulatory molecules, vaccinations and methods of immunogenic tumour priming including radiofrequency ablation. Finally, we discuss reasons why peri-operative and in particular neoadjuvant combination treatments are likely to be most effective and should be considered for early clinical trials.

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Stage III NSCLC: How many patients are really suitable for radical treatment approaches?

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e17532 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e17532-e17532

Author(s):

Humaid Obaid Al-Shamsi ◽

Peter Michael Ellis

Keyword(s):

Clinical Trials ◽

Stage Iiib ◽

Stage Iii ◽

Published Data ◽

Stage Iiia ◽

Eligibility Criteria ◽

Treatment Approaches ◽

Radical Treatment ◽

Stage Iii Nsclc ◽

Nsclc Patients

e17532 Background: Stage III NSCLC represents a heterogeneous population. Patients with good performance status (PS) and weight loss < 10% (WL<10) are generally considered for radical treatment with chemoradiation or trimodality approaches. Outcome data from Cancer Care Ontario show 30% of stage III NSCLC (6th edition TNM) patients receive chemoradiation.There is significant variation between local health networks. We examined the proportion of patients with stage III NSCLC suitable for radical treatment. Methods: We conducted a retrospective cohort study of patients diagnosed with stage III NSCLC at the Juravinski Cancer Center from July 2007 to June 2009. Demographic, pathologic and treatment data were abstracted from patients’ records. The primary outcome was the proportion of stage III NSCLC patients eligible for radical treatment. We also compared patients treated radically versus palliatively. Results: 159 stage III NSCLC patients (staged by 6th edition TNM) were seen. The median age was 69 yrs (sd 12) with 58% men and 42% women. There were 40% stage IIIA, 37% IIIB and 23% IIIB (wet). 61 (38%) patients were treated with radical intent and 98 (62%) were treated palliatively. Reasons for palliative treatment approach were WL >10% (7%), PS >2 (10% ), both WL >10% and PS >2 (20%), significant comorbidities (9%),patient declined (9%) and stage IIIB wet(23 %).The median OS for patients treated radically was 23.3 months v 7.1 months for those treated palliatively. Stage IIIA patients treated radically had better OS than IIIB (27m v 14m). Patients with poor PS, or WL>10% had similar OS to patients with wet stage IIIB (7.1m v 7.2m), whereas the survival of patients with poor PS and WL >10% was worse (3m). Conclusions: Using eligibility criteria from clinical trials of stage III NSCLC, only 40% of patients appear eligible for radical treatment approaches. Our data are consistent with published data. Significant WL>10% or poor PS (>2) predicted poor outcome. Combined WL>10% and poor PS predicted a very poor prognostic group. Criteria for radical treatment of stage III NSCLC should not be extrapolated beyond the eligibility criteria used in clinical trials.

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The Landscape of Novel Therapeutics and Challenges in Glioblastoma Multiforme: Contemporary State and Future Directions

Pharmaceuticals ◽

10.3390/ph13110389 ◽

2020 ◽

Vol 13 (11) ◽

pp. 389 ◽

Cited By ~ 1

Author(s):

Karam Khaddour ◽

Tanner Johanns ◽

George Ansstas

Keyword(s):

Clinical Trials ◽

Targeted Therapy ◽

Glioblastoma Multiforme ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Tumor Biology ◽

Adoptive Cell Transfer ◽

High Morbidity ◽

Future Directions ◽

Treatment Approaches

Background: Glioblastoma multiforme is a malignant intracranial neoplasm that constitutes a therapeutic challenge because of the associated high morbidity and mortality given the lack of effective approved medication and aggressive nature of the tumor. However, there has been extensive research recently to address the reasons implicated in the resistant nature of the tumor to pharmaceutical compounds, which have resulted in several clinical trials investigating promising treatment approaches. Methods: We reviewed literature published since 2010 from PUBMED and several annual meeting abstracts through 15 September 2020. Selected articles included those relevant to topics of glioblastoma tumor biology, original basic research, clinical trials, seminal reviews, and meta-analyses. We provide a discussion based on the collected evidence regarding the challenging factors encountered during treatment, and we highlighted the relevant trials of novel therapies including immunotherapy and targeted medication. Results: Selected literature revealed four main factors implicated in the low efficacy encountered with investigational treatments which included: (1) blood-brain barrier; (2) immunosuppressive microenvironment; (3) genetic heterogeneity; (4) external factors related to previous systemic treatment that can modulate tumor microenvironment. Investigational therapies discussed in this review were classified as immunotherapy and targeted therapy. Immunotherapy included: (1) immune checkpoint inhibitors; (2) adoptive cell transfer therapy; (3) therapeutic vaccines; (4) oncolytic virus therapy. Targeted therapy included tyrosine kinase inhibitors and other receptor inhibitors. Finally, we provide our perspective on future directions in treatment of glioblastoma. Conclusion: Despite the limited success in development of effective therapeutics in glioblastoma, many treatment approaches hold potential promise including immunotherapy and novel combinational drugs. Addressing the molecular landscape and resistant immunosuppressive nature of glioblastoma are imperative in further development of effective treatments.

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Macrophage-derived granulin drives resistance to immune checkpoint inhibition in metastatic pancreatic cancer

10.1101/234906 ◽

2017 ◽

Cited By ~ 1

Author(s):

Valeria Quaranta ◽

Carolyn Rainer ◽

Sebastian R. Nielsen ◽

Meirion Raymant ◽

Muhammad Shamsher Ahmed ◽

...

Keyword(s):

Pancreatic Cancer ◽

T Cell ◽

Immune Checkpoint ◽

Checkpoint Inhibitors ◽

Tumour Microenvironment ◽

Ductal Adenocarcinoma ◽

Metastatic Tumour ◽

Metastatic Progression ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition

AbstractThe ability of disseminated cancer cells to evade the immune response is a critical step for efficient metastatic progression. Protection against an immune attack is often provided by the tumour microenvironment that suppresses and/or excludes cytotoxic CD8+ T cells. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive metastatic disease with unmet needs, yet the immuno-protective role of the metastatic tumour microenvironment in pancreatic cancer is not completely understood. In this study we find that macrophage-derived granulin contributes to cytotoxic CD8+ T cell exclusion in metastatic livers. Mechanistically, we find that granulin expression by macrophages is induced in response to colony stimulating factor-1. Genetic depletion of granulin reduces the formation a fibrotic stroma, thereby allowing T cell entry at the metastatic site. While metastatic PDAC tumours are largely resistant to anti-PD-1 therapy, blockade of PD-1 in granulin depleted tumours restored the anti-tumour immune defence and dramatically decreased metastatic tumour burden. These findings suggest that targeting granulin may serve as a potential therapeutic strategy to restore CD8+ T cell infiltration in metastatic PDAC, thereby converting PDAC metastatic tumours, which are refractory to immune checkpoint inhibitors, into tumours that respond to immune checkpoint inhibition therapies.

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Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma

Journal of Hematology & Oncology ◽

10.1186/s13045-020-00958-3 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Yunzhen Qian ◽

Yitao Gong ◽

Zhiyao Fan ◽

Guopei Luo ◽

Qiuyi Huang ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Checkpoint Inhibitors ◽

Tumour Microenvironment ◽

Future Trend ◽

Ductal Adenocarcinoma ◽

Precision Oncology ◽

Clinical Value ◽

Genetic Event ◽

Molecular Alterations ◽

Tumour Suppressors

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a malignancy characterized by a poor prognosis and high mortality rate. Genetic mutations and altered molecular pathways serve as targets in precise therapy. Using next-generation sequencing (NGS), these aberrant alterations can be identified and used to develop strategies that will selectively kill cancerous cells in patients with PDAC. The realization of targeted therapies in patients with PDAC may be summarized by three approaches. First, because oncogenes play a pivotal role in tumorigenesis, inhibition of dysregulated oncogenes is a promising method (Table 3). Numerous researchers are developing strategies to target oncogenes, such as KRAS, NRG1, and NTRK and related molecules, although most of the results are unsatisfactory. Accordingly, emerging strategies are being developed to target these oncogenes, including simultaneously inhibiting multiple molecules or pathways, modification of mutant residues by small molecules, and RNA interference. Second, researchers have attempted to reactivate inactivated tumour suppressors or modulate related molecules. TP53, CDKN2A and SMAD4 are three major tumour suppressors involved in PDAC. Advances have been achieved in clinical and preclinical trials of therapies targeting these three genes, and further investigations are warranted. The TGF-β-SMAD4 signalling pathway plays a dual role in PDAC tumorigenesis and participates in mediating tumour-stroma crosstalk and modulating the tumour microenvironment (TME); thus, molecular subtyping of pancreatic cancer according to the SMAD4 mutation status may be a promising precision oncology technique. Finally, genes such as KDM6A and BRCA have vital roles in maintaining the structural stability and physiological functions of normal chromosomes and are deficient in some patients with PDAC, thus serving as potential targets for correcting these deficiencies and precisely killing these aberrant tumour cells. Recent clinical trials, such as the POLO (Pancreas Cancer Olaparib Ongoing) trial, have reported encouraging outcomes. In addition to genetic event-guided treatment, immunotherapies such as chimeric antigen receptor T cells (CAR-T), antibody-drug conjugates, and immune checkpoint inhibitors also exhibit the potential to target tumours precisely, although the clinical value of immunotherapies as treatments for PDAC is still limited. In this review, we focus on recent preclinical and clinical advances in therapies targeting aberrant genes and pathways and predict the future trend of precision oncology for PDAC.

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