Immunomodulatory drug development is trending toward increasingly complex modalities as science advances and more effective and safe immunotherapies are needed. Immunomodulatory drugs are at the forefront for the treatment of various types of cancer, infectious diseases, and numerous autoimmune diseases, including rheumatoid arthritis, type I diabetes, lupus, and multiple sclerosis. As the complexity of these therapeutics increases, so must the sophistication of the bioanalytical assays designed to either quantify them or measure their impact on the patient.

In this issue, we review common classes of immunomodulators, bioanalytical methods used to quantify them, and their associated biomarkers. We further present two scenarios that address the complexities of bioanalysis for immunomodulators and practical considerations to ensure quality bioanalysis to inform pharmacokinetic (PK), pharmacodynamic (PD), and safety data in clinical trials.

Issue 41 — Immunomodulation Assessments for Clinical Trials

BUFFALO, NY - November 4, 2024 – A new #casereport was #published in Oncotarget's Volume 15 on October 11, 2024, entitled “A case of adenosquamous pancreatic cancer with a KRAS G12C mutation with an exceptional response to immunotherapy.”

This case report highlights a remarkable and unexpected response to immunotherapy in a patient with metastatic adenosquamous pancreatic cancer (ASCP), a rare and aggressive form of pancreatic cancer. The study, led by Murtaza Ahmed, Brent K. Larson, Arsen Osipov, Nilofer Azad, and Andrew Hendifar from Cedars-Sinai Medical Center and Johns Hopkins University, provides new hope for ASCP patients, who are traditionally underserved by current treatment options.

The team documented a 68-year-old male with metastatic ASCP carrying a KRAS G12C mutation. Unexpectedly, after limited success with standard therapies, the patient’s cancer responded significantly to pembrolizumab, a type of immune checkpoint inhibitor, despite the absence of typical markers indicating suitability for immunotherapy.

Pancreatic cancer remains one of the most lethal cancer types, with few advancements in effective treatments for its rarer forms, such as ASCP, which accounts for only 1-10% of all pancreatic cancer cases. Traditionally, ASCP has been treated with chemotherapy based on protocols for the more common pancreatic ductal adenocarcinoma, despite the distinct tumor characteristics. 

This case suggests that ASCP’s unique tumor microenvironment may make it more receptive to immunotherapy. Researchers are hopeful that this new understanding will drive clinical trials focused on immunotherapy specifically for ASCP patients, potentially offering new options for those with limited treatment success. 

“To that point, there is an active multi-center phase 2 trial investigating outcomes and responses to ICI in patients with metastatic or unresectable ASCP or ampullary cancer.” 

In conclusion, this report signals a potential shift in the treatment of rare and aggressive pancreatic cancer subtypes like ASCP. As oncology increasingly embraces personalized medicine, cases like this one open new avenues for patients who were not responsive to traditional therapies, potentially transforming the management of previously intractable cancers.

DOI - https://doi.org/10.18632/oncotarget.28659

Correspondence to - Andrew Hendifar - andrew.hendifar@cshs.org

Video short - https://www.youtube.com/watch?v=VnfohGvfMoM

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Keywords - cancer, pancreatic cancer, immunotherapy, metastasis

About Oncotarget 

Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Oncotarget

Immunotherapy Success in KRAS G12C Adenosquamous Pancreatic Cancer

BUFFALO, NY - November 12, 2024 – A new #review was #published in Oncotarget's Volume 15 on November 7, 2024, entitled “Understanding the interplay between extracellular matrix topology and tumor-immune interactions: Challenges and opportunities.”

This comprehensive review by researchers Yijia Fan, Alvis Chiu, Feng Zhao, and Jason T. George from Texas A&M University, Rice University, and MD  Anderson Cancer Center sheds light on how the structural properties of the extracellular matrix (ECM) within tumors impact immune cell behavior and influence the effectiveness of cancer immunotherapies. The ECM, a network of proteins surrounding cells, often transforms in cancer, becoming denser and more aligned. These changes create physical barriers that can prevent immune cells, especially T cells, from effectively accessing and attacking tumors, thereby limiting the success of immunotherapies.

The team emphasizes the role of specific ECM configurations, known as Tumor-Associated Collagen Signatures (TACS), in cancer progression and immune evasion. TACS1 and TACS2 patterns create "immune deserts" around tumors, limiting immune cell movement and preventing T cells from recognizing and attacking cancer cells, which is essential for successful immunotherapy. In advanced stages, TACS3 aligns ECM fibers in ways that both promote tumor spread and create additional barriers, further obstructing immune cell access to the tumor.

These insights lead the way for ECM-targeted therapies designed to modify these barriers, potentially transforming “cold” (immune-non-responsive) tumors into “hot” (immune-responsive) ones, thereby improving immune cell infiltration and enhancing treatment outcomes. 

“Understanding the complex interplay is relevant for developing more accurate model of tumor evasion and the identification of corresponding therapeutic intervention.”


The review highlights advanced computational models that simulate interactions between the ECM, immune cells, and tumors, offering valuable insights for developing ECM-targeted therapies. These models illustrate how modifying ECM properties could enhance immune cell migration and function, potentially overcoming immune resistance and expanding the effectiveness of immunotherapies.

The authors also suggest that targeting ECM structure could significantly enhance the effectiveness of immunotherapy, especially for cancers like breast, pancreatic, and ovarian, which often feature dense ECM regions. By reshaping the ECM, such treatments could enable immune cells to access previously unreachable tumor areas, presenting a promising strategy to combat tumors that are resistant to standard therapies.

In conclusion, the review underscores the need for continued research into ECM-focused strategies, which could support more integrated approaches to cancer treatment. By targeting the ECM’s physical barriers and immune evasion mechanisms, these strategies hold promise for improving outcomes in difficult-to-treat cancers.

DOI - https://doi.org/10.18632/oncotarget.28666

Correspondence to - Jason T. George - jason.george@tamu.edu

Video short - https://www.youtube.com/watch?v=7Wm-SMLJadk

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Extracellular Matrix and Tumor-Immune Interactions: Challenges & Opportunities

BUFFALO, NY - December 3, 2024 – A new #review was #published in Oncotarget's Volume 15 on November 22, 2024, entitled “Mesenchymal stem cells - the secret agents of cancer immunotherapy: Promises, challenges, and surprising twists." 

Authored by Theia Minev, Shani Balbuena, Jaya Mini Gill, Francesco M. Marincola, Santosh Kesari, and Feng Lin from CureScience Institute, Sonata Therapeutics, and Pacific Neuroscience Institute and Providence Saint John’s Health Center, this review explores the potential role of mesenchymal stem cells (MSCs) in cancer treatment. These stem cells can naturally target tumors and deliver therapeutic agents directly to cancer cells, potentially improving treatment outcomes while reducing side effects commonly associated with traditional therapies like chemotherapy. However, the authors also note significant challenges, pointing out that under certain conditions, MSCs may unintentionally promote tumor growth, highlighting the need for careful therapeutic design.

MSCs are cells that can develop in different types of tissues, such as bone, fat, or cartilage, and act as natural repair agents. What makes them particularly special is their ability to respond to biological signals, like inflammation, which is often present in cancer. This enables them to locate tumors, and once there, they can deliver cancer treatments directly to the affected area.

Clinical trials are already investigating MSC-based treatments for cancers such as brain tumors, melanoma, and ovarian cancer. Some results are promising, showing that MSCs can effectively deliver treatments and boost the immune system’s fight against cancer. However, other trials have also revealed the complexities of MSC behavior, including variability in their effects and the potential to create conditions that support tumor growth. 

“This variability may be due to the tumor immune microenvironment’s effects, where immune cells are inhibited by various factors, creating a conducive environment for tumor growth.” 

The authors also suggest that “Developing personalized MSC therapies tailored to the specific characteristics of a patient’s tumor and immune system could enhance the efficacy and safety of MSC-based treatments.” Achieving this requires a deeper understanding of how MSCs interact with cancer cells and their surrounding environment.

In conclusion, this review highlights both the potential and challenges of (MSCs in cancer therapy. With ongoing research and technological advancements, MSCs could become a key component of personalized cancer treatments, offering new hope for patients worldwide.

DOI - https://doi.org/10.18632/oncotarget.28672

Correspondence to - Feng Lin - flin@curescience.org

Video short - https://www.youtube.com/watch?v=Wwc3zDDitlc

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About Oncotarget 

Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Mesenchymal Stem Cells in Cancer Immunotherapy: Promises and Challenges

In this episode of the In Vivo podcast, Harvard immunologist and co-founder of early-stage biotech Corner Therapeutics, Jonathan Kagan, talks about harnessing the power of the innate immune system by weaponizing dendritic cells and creating immunotherapies that are safer and more durable.

The Future of Immunotherapy

Juho Jalkanen, CEO of Faron Pharma, discusses the importance of addressing unmet medical needs in cancer through breaking treatment resistance and developing long-term solutions. In Vivo questions the current progress of their lead asset BEXMAB and its potential moving forward.

A “Game Changer” For The High-Risk MDS Patient Population

BUFFALO, NY - January 21, 2025 – A new #research paper was #published in Oncotarget's Volume 16 on January 20, 2025, titled “Anti-correlation of KLRG1 and PD-1 expression in human tumor CD8 T cells."

The study, authored by Dr. Steven A. Greenberg from Harvard Medical School, has discovered a potential new way to improve cancer treatment by studying two key molecules found in immune cells: KLRG1 and PD-1. Analysis of data from cancer patients and healthy individuals revealed that these molecules work in opposite ways in cancer-fighting cells, suggesting that targeting both at the same time could enhance the effectiveness of cancer immunotherapy.

“Much effort in the field of immuno-oncology has involved the study of combination therapies, including combinations involving blockade of more than one T cell inhibitory receptor.”

The immune system helps fight cancer through specialized cells called T cells. Treatments known as checkpoint inhibitors, which block proteins like PD-1, have been successful in helping these cells attack cancer. However, combining different checkpoint inhibitors has not always provided the expected improvements. 

This new research focuses on KLRG1, a lesser-known protein, and its relationship with PD-1. The findings suggest that targeting both markers simultaneously could create a stronger and more effective immune response against cancer. Most existing immunotherapy treatments focus only on blocking PD-1, which is commonly found in “exhausted” T cells that struggle to fight cancer. In contrast, KLRG1 is linked to more active, mature T cells that are better at attacking tumors. By blocking both PD-1 and KLRG1, new treatment strategies could help patients with hard-to-treat cancers, such as lung cancer, melanoma, and colorectal cancer.

KLRG1 has not been widely studied in cancer immunotherapy, but this research highlights its potential to revolutionize treatment strategies. While current combinations of checkpoint inhibitors have shown only limited improvements, using therapies that target both PD-1 and KLRG1 could lead to more significant and long-lasting benefits.

“Whereas much of the T cell inhibitory drug development efforts over the last decade have been focused on combinations of expression-correlated inhibitory receptor targets, the targeting of anti-correlated inhibitory receptors has greater potential to produce supra-additive benefit, and KLRG1 has this distinct property.”

Further studies and clinical trials are needed to explore how combining PD-1 and KLRG1 treatments could benefit different types of cancer. If successful, this strategy could open the door for the creation of new combined immunotherapies.

DOI - https://doi.org/10.18632/oncotarget.28679

Correspondence to - Steven A. Greenberg - sagreenberg@bwh.harvard.edu

Video short - https://www.youtube.com/watch?v=PME2xfyYN18

About Oncotarget 

Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Anti-Correlation Between KLRG1 and PD-1 in Tumor CD8 T Cells

An unexpected link between KLRG1 and PD-1, two key immune system proteins, was revealed in a study recently published in Oncotarget. This discovery could help explain why some cancer immunotherapy treatments are less effective for certain patients and lead to new therapeutic strategies.

How the Immune System Fights Cancer

The immune system is a powerful defense mechanism against cancer, with CD8 T cells acting as the primary soldiers. These specialized immune cells identify and destroy tumor cells. However, cancer can cleverly evade this attack by manipulating immune checkpoints—natural “breaks” on the immune system that prevent it from overreacting and damaging healthy tissue.

One of the most studied checkpoints is PD-1 (Programmed Death-1), a receptor on T cells that acts as an “off switch” when activated by tumor cells. This mechanism suppresses the immune response, allowing cancer to grow without control. In response, researchers have developed treatments called PD-1 inhibitors, which block this “off switch” and keep T cells active. 

The Study: Investigating KLRG1 and PD-1 in Tumor-Fighting T Cells

In the study titled “Anti-correlation of KLRG1 and PD-1 expression in human tumor CD8 T cells,” Dr. Steven A. Greenberg from Harvard Medical School analyzed publicly available gene expression data from various cancer types, including lung cancer, melanoma, and colorectal cancer. His goal was to identify immune-related proteins that could complement existing therapies, such as PD-1 inhibitors.

Full blog - https://www.oncotarget.org/2025/01/28/a-new-approach-for-cancer-treatment-the-surprising-relationship-between-klrg1-and-pd-1/

Paper DOI - https://doi.org/10.18632/oncotarget.28679

Correspondence to - Steven A. Greenberg - sagreenberg@bwh.harvard.edu

Video short - https://www.youtube.com/watch?v=PME2xfyYN18

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Keywords - cancer, immunotherapy, KLRG1

About Oncotarget 

Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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A New Approach for Cancer Treatment: The Surprising Relationship Between KLRG1 and PD-1

BUFFALO, NY - March 21, 2025 – A new #editorial was #published in Oncotarget, Volume 16, on March 13, 2025, titled “No disease left behind."

In this editorial, Dr. Muzamil Arshad from the University of Chicago Medical Center and colleagues highlight a growing concern in cancer care: radiotherapy may leave behind microscopic cancer even when scan images suggest the tumor is gone. The authors argue that this “residual disease” is more common than expected and is linked to worse long-term outcomes. Their perspective calls for a rethinking of how treatment success is judged and how cancer is followed up after therapy.

Radiotherapy, especially a form known as stereotactic ablative radiotherapy (SABR), is widely used to treat cancers in the lung, liver, prostate, and other organs.  SABR delivers high-dose radiation with outstanding precision and often shows excellent results on scans. However, the authors highlight that relying only on imaging may not provide a complete picture. Months or even years later, follow-up biopsies frequently reveal cancer cells that scan imaging tests were unable to identify.

“Residual cancer is identified on histology in 40% of lung, 57–69% of renal cell, 7.7–47.6% of prostate and 0–86.7% of hepatocellular carcinoma.”

This gap between what scans show and what tissue analysis finds can have serious consequences. Studies across several cancer types have shown that patients with residual disease—even if small—are more likely to experience cancer recurrence and shorter survival. This pattern holds true for rectal, cervical, prostate, and liver cancers, among others. In some cases, not  destroying the tumor completely may allow it to spread to distant organs.

The authors point out that a complete response on scan imaging does not necessarily indicate the complete disappearance of the tumor. This mismatch can mislead both clinicians and patients into thinking treatment was more successful than it truly was. The editorial encourages more regular use of biopsy-based tests and new strategies to increase the true effectiveness—or “ablative power”—of SABR.

They also discuss promising approaches to improve outcomes, including increasing radiation doses and combining radiotherapy with other therapies, such as immune checkpoint inhibitors. While some trials have shown better tumor control with these combinations, results have not been consistent, and more research is needed to refine these strategies.

In summary, this editorial encourages the cancer care community to look beyond the scan images. Residual cancer may remain even when imaging looks clear, and recognizing this hidden threat is key to improving long-term outcomes. The goal is not just to shrink tumors on screen but to fully eliminate the disease.

DOI - https://doi.org/10.18632/oncotarget.28700

Correspondence to - Muzamil Arshad - muzamil.arshad@uchicagomedicine.org

Video short - https://www.youtube.com/watch?v=XC0XNjJjC2o

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Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

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Clear Scans Can Be Misleading: Residual Cancer Linked to Worse Outcomes

In this third podcast by the West Yorkshire and Harrogate Cancer Alliance, Sue Ormesher, Amanda Procter, Sadie Smith and Jason Pawluk talk about Maggie's Cancer Care Support Centre and in particular a new service in Leeds. ‘Getting Started’ is available to anyone who is about to start immunotherapy or chemotherapy. Sessions, which can also be attended by family and friends, help people understand the treatment, the potential side effects, how to manage and what to do if they're struggling.

Cancer Alliance Maggie's Podcast

Citeline places biopharma and medical device professionals, and those who focus on these industries, at the forefront of knowledge and insight, by providing the perfect combination of news and information together with penetrating insight and analysis. Citeline is a leader in the field of healthcare industry information.

Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form and then quickly released to Pubmed.

Oncotarget is now indexed by MEDLINE, PubMed and PMC/PubMed.

Read about the Oncotarget Scientific Integrity Process: https://www.oncotarget.com/scientific_integrity/

West Yorkshire Health and Care Partnership is an ‘Integrated Care System’. We work in partnership with NHS organisations, councils, Healthwatch, charities and the community voluntary and social enterprise sector to improve the health and wellbeing of local people living in our five local places: 
Bradford district & Craven, Calderdale, Kirklees, Leeds, and Wakefield

As an end-to-end CRO/CDMO, we have expert knowledge in all early stages of drug development, and we’re sharing that knowledge with you in The Altascientist: The Audiobook. 

Each issue is a deep dive into a specific area of early-phase drug development, providing insider tips, considerations, and case studies. 


Altasciences is a drug development solution company offering pharmaceutical and biotechnology companies a proven, flexible approach to preclinical and clinical pharmacology studies, including formulation, manufacturing, and analytical services.

New tracks tagged #immunotherapy