Tagged: immunotherapy

Immune Checkpoint Inhibitors May Improve Outcomes in High-Risk Solid Tumors

May 20, 2026

“This systematic review and meta-analysis of 13 randomized controlled trials including 9,850 patients shows that adjuvant PD-1 and PD-L1 inhibitors improve disease-free and distant metastasis-free survival in patients with high-risk solid tumors.”

Cancer immunotherapy has transformed the treatment landscape for many advanced cancers over the past decade. Drugs targeting the PD-1 and PD-L1 pathways are now widely used across several tumor types, helping the immune system recognize and attack cancer cells more effectively. However, researchers are still working to understand how beneficial these therapies may be when used earlier in the disease course, particularly after surgery in patients with high-risk solid tumors.

A research paper on this topic was published in Volume 17 of Oncotarget titled “Efficacy and safety of PD-1/ PD-L1 inhibitors as adjuvants in the treatment of patients with solid cancers: A systematic review and meta-analysis of randomized controlled trials.”

Understanding Adjuvant Immunotherapy

Adjuvant therapy refers to treatment given after primary treatment, such as surgery, to help reduce the risk of cancer recurrence. While PD-1 and PD-L1 inhibitors are already established therapies for several advanced cancers, their role in earlier-stage solid tumors remains an active area of investigation.

To better evaluate their effectiveness and safety, the researchers conducted a systematic review and meta-analysis of 13 randomized controlled trials published between 2021 and 2023. Altogether, the analysis included 9,850 patients with cancers such as renal cell carcinoma, melanoma, non-small cell lung cancer, esophageal cancer, gastroesophageal junction cancer, and urothelial carcinoma.

Improved Disease-Free Survival

The analysis found that adjuvant PD-1 and PD-L1 inhibitors were associated with improved disease-free survival and distant metastasis-free survival compared with control groups. In several studies, therapies such as pembrolizumab and nivolumab reduced the likelihood of cancer recurrence or distant metastasis in patients with high-risk tumors.

The authors also noted that treatment responses varied depending on cancer type and therapeutic regimen, highlighting the complexity of immune responses across different tumor environments.

Balancing Benefits and Side Effects

Although the therapies improved several important clinical outcomes, they were also associated with increased adverse events. Commonly reported side effects included fatigue, diarrhea, rash, nausea, pruritus, hypothyroidism, and arthralgia.

The study found that treatment-related adverse events occurred more frequently in patients receiving PD-1 and PD-L1 inhibitors compared with control groups. The authors emphasized that careful monitoring and long-term follow-up remain important when using these therapies in the adjuvant setting.

Why Longer Follow-Up Matters

One important finding from the analysis was that, despite improvements in disease-free survival, a clear overall survival benefit has not yet been consistently demonstrated. According to the authors, this may partly reflect the relatively short follow-up periods currently available in many of the trials.

The researchers also noted that the number of studies within each cancer subtype remains limited, making cancer-specific conclusions more difficult at this stage.

Looking Ahead

This study highlights the growing potential of adjuvant immunotherapy in solid cancers while also underscoring the need for longer-term data and more precise patient selection strategies. Future studies will likely focus on identifying which patients benefit the most, refining biomarker-guided treatment approaches, and improving management of immune-related side effects.

Still, the findings suggest that PD-1 and PD-L1 inhibitors may play an increasingly important role in reducing recurrence risk in selected patients with high-risk solid tumors.

The authors concluded that larger trials with longer follow-up are needed to better define which patient groups derive the greatest benefit.

Click here to read the full research paper published in Oncotarget.

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Oncotarget is an open-access, peer-reviewed journal that has published primarily oncology-focused research papers since 2010. These papers are available to readers (at no cost and free of subscription barriers) in a continuous publishing format at Oncotarget.com.

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Immunotherapy Response in Pancreatic Cancer: What a New Study Reveals

September 11, 2025

“Identification and analyses of exceptional responders could eventually offer hints as to why PC is resistant to immunotherapy.”

Immunotherapy is not usually effective against pancreatic cancer (PC), but a new study published in Oncotarget (Volume 16, 2025) highlights rare cases where it did help. These examples, though uncommon, may offer valuable insights for future treatment.

Pancreatic Cancer and Immunotherapy

Pancreatic cancer is often diagnosed at an advanced stage, which limits treatment options and contributes to its poor prognosis. While chemotherapy remains the standard treatment, it usually offers only modest benefits in terms of survival. Immunotherapy—an approach that activates the immune system to fight cancer—has been effective in other cancers but has shown limited success in PC.

This is largely due to the tumor’s ability to suppress immune responses and create an environment that protects it from attack. Currently, these drugs are only approved for a small subset of patients whose tumors have a specific genetic feature called high microsatellite instability (MSI-high), found in just 1 to 2 percent of cases.

The Study: Pancreatic Cancer Immunotherapy Responders

The study, titled “Exceptional responders to immunotherapy in pancreatic cancer: A multi-institutional case series of a rare occurrence,” was led by first author Kavin Sugumar and corresponding author Jordan M. Winter, from University Hospitals Seidman Cancer Center.

The researchers examined medical records from 14 patients with pancreatic ductal adenocarcinoma (PDAC) who had responded unexpectedly well to immune checkpoint inhibitors—drugs that help reactivate immune cells to attack cancer. The drugs included PD-1 inhibitors such as pembrolizumab and nivolumab, CTLA-4 inhibitors like ipilimumab, and agents targeting tumor-associated macrophages. To find these rare cases, the research team contacted 471 oncologists from 91 major U.S. cancer centers between 2020 and 2021.

Most of the patients in this study had already tried chemotherapy, without lasting success. These patients received immunotherapy alone. They were selected because they showed either a reduction in tumor size on imaging or a drop in CA 19-9, a blood marker used to monitor PC.

This case series is the largest to focus exclusively on PC patients who responded well to immunotherapy. By excluding those who received chemotherapy simultaneously, the study aimed to isolate the effects of immune-based treatments alone.

The Results: Immunotherapy Shows Effectiveness in Both MSI-High and MSI-Stable Pancreatic Cancer

After starting immunotherapy, 82% of the patients showed a partial response, meaning their tumors became smaller. Around one-third of the patients had a meaningful decrease in CA 19-9 levels. On average, their disease remained stable for about 12 months, which is longer than typically seen with other treatments at this stage. Some patients lived for more than two years after beginning immunotherapy.

What stood out most was that more than half of these patients did not have MSI-high tumors. This challenges the current understanding that only MSI-high patients are likely to benefit from immunotherapy and suggests that other, less well-understood factors may also play a role.

The Impact: Expanding the Role of Immunotherapy in Pancreatic Cancer

Although this study includes only a small number of patients, the results suggest that immunotherapy may benefit more individuals with PC than previously assumed. While the standard of care still centers on chemotherapy, this case series shows that a small but meaningful group of patients—some without the usual MSI-high genetic marker—can respond well to immune-based treatments. These observations support the idea that immunotherapy may have a broader role in PC care.

Future Perspectives and Conclusion

These findings highlight the need to understand why certain PC patients respond to immunotherapy despite lacking known predictive markers like MSI-high. Exploring tumor biology, immune interactions, and patient-specific characteristics may help identify new indicators of response.

Although immunotherapy remains ineffective for most PC cases, rare outcomes like those in this study offer valuable clues. Investigating these exceptions more closely could support the development of more personalized and effective treatment approaches.

Click here to read the full research paper in Oncotarget.

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Immunotherapy Safety for Hepatocellular Carcinoma in Latin America: Insights from a Real-World Study

July 2, 2025

“Latin America has been underrepresented in trials evaluating immunotherapy for hepatocellular carcinoma (HCC).”

Liver cancer, especially hepatocellular carcinoma (HCC), remains a major health concern worldwide. In Latin America, the situation becomes more difficult due to limited access to advanced treatments and the high prevalence of underlying liver diseases. A recent research paper, published in Volume 16 of Oncotarget by researchers from Argentina, Brazil, Chile, and Colombia, offers valuable insights into how patients in the region respond to a widely used immunotherapy regimen. This real-world study explores both the effectiveness of treatment and the risks of immune-related side effects.

Understanding Hepatocellular Carcinoma: Why It is So Difficult to Treat

Hepatocellular carcinoma is often diagnosed at an advanced stage and frequently occurs in people with pre-existing liver conditions such as cirrhosis. Standard treatments like surgery or local therapies are not always possible in these cases. In recent years, the combination of two drugs—atezolizumab and bevacizumab—has shown promise in extending survival. However, most of the evidence comes from controlled clinical trials that may not represent the realities faced by healthcare providers and patients in Latin America.

The Study: Immunotherapy for Hepatocellular Carcinoma in Latin America

In a multicenter study titled “Immune-mediated adverse events following atezolizumab and bevacizumab in a multinational Latin American cohort of unresectable hepatocellular carcinoma,” led by Leonardo Gomes da Fonseca from Hospital das Clínicas, Universidade de São Paulo, Brazil, and Federico Piñero from Hospital Universitario Austral, Argentina, researchers aimed to fill that gap. The study included 99 patients with advanced HCC from Argentina, Brazil, Chile, and Colombia. All patients received the combination of atezolizumab and bevacizumab. The main objectives were to assess how frequently immune-related side effects, known as immune-related adverse events (irAEs), occurred and whether these events affected overall survival.

The Results: Immune-Related Adverse Events

Immunotherapy works by boosting the immune system to fight cancer. However, this can also lead to unintended effects where the immune system attacks healthy tissues. These irAEs can range from mild symptoms to serious conditions like liver inflammation, which can be particularly dangerous for patients whose liver function is already damaged.

In this study, the median overall survival was 17 months, a result consistent with international clinical trials. About 18% of patients developed irAEs, most commonly hepatitis, thyroiditis, and nephritis. Nearly half of these cases required medical treatment such as corticosteroids. Even so, only about half of the irAEs were completely resolved. Importantly, the occurrence of irAEs did not appear to reduce overall survival, suggesting that while these side effects require attention, they are manageable.

An additional finding was that patients with higher levels of alpha-fetoprotein (AFP), a marker often used to assess liver cancer severity, were more likely to develop irAEs. This could help clinicians identify which patients need closer monitoring during treatment.

Implications for Hepatocellular Carcinoma Care in Latin America

This is one of the few studies assessing how HCC patients in Latin America respond to immunotherapy in everyday clinical settings. The results support the use of atezolizumab and bevacizumab in the region but also point out the importance of being prepared to detect and manage side effects. Building medical capacity for early identification and treatment of irAEs is especially important for patients with weaker liver function.

Future Perspectives and Conclusion

Although immune-related side effects did not seem to affect survival in this study, they add another layer of complexity to HCC treatment. More research is needed to understand which patients are most at risk and how to prevent these side effects. For the moment, this study provides useful information for clinicians and healthcare systems aiming to safely expand access to immunotherapy in Latin America for HCC.

Click here to read the full research paper in Oncotarget.

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Exploring a Combined Approach: Radiation and Immunotherapy in Bladder Cancer

June 16, 2025

“Different treatment strategies are required for the non-muscle-invasive, muscle-invasive, and metastatic stages of bladder cancer.”

Bladder cancer remains a significant clinical concern, with more than 85,000 new diagnoses and nearly 19,000 deaths reported annually in the United States. While current treatments like surgery, chemotherapy, and radiation can be effective for early-stage disease, many patients with advanced or recurrent cancer face limited options.

A recent review, published in Oncotarget by researchers from the University of California, Irvine, analyzes the growing body of evidence supporting the combination of radiation therapy and immunotherapy for bladder cancer. Led by Nazmul Hasan, the work synthesizes clinical data and biological mechanisms that suggest this strategy could enhance anti-tumor responses in specific patient groups.

Understanding Bladder Cancer and Treatment Limitations

The type of treatment for bladder cancer depends on how far the disease has progressed. For early-stage cases, tumors are typically managed with transurethral resection followed by local therapies such as BCG (Bacillus Calmette-Guérin) to reduce the risk of recurrence.

If the tumor has grown deeper into the bladder wall (known as muscle-invasive bladder cancer), more aggressive treatment is needed. This often involves complete bladder removal (cystectomy) or using a combination of radiation, chemotherapy, and surgery to attempt bladder preservation.

Despite these interventions, recurrence remains common, particularly in more advanced stages. Immunotherapy, which helps the immune system recognize and attack cancer cells, has led to improved outcomes in some bladder cancer patients, yet overall response rates are limited. Radiation, while effective for localized tumors, generally does not achieve long-lasting results when used alone. Because of these limitations, researchers are now studying ways to combine treatments, like radiation and immunotherapy, to improve therapeutic outcomes.

Synthesizing Clinical Data

The review, titled “Advancements in bladder cancer treatment: The synergy of radiation and immunotherapy,” focuses on how these two modalities may interact to enhance anti-tumor activity. Radiation is known to induce immunogenic cell death, releasing tumor-associated antigens that stimulate an immune response. Immunotherapy enhances this immune activation by blocking checkpoint pathways—such as PD-1 or CTLA-4—that tumors use to evade immune detection.

The authors highlight several studies and clinical trials that have explored this combination in clinical practice, including BTCRC-GU15-023, ANZUP, and INTACT trials. These trials vary in design but all examine ways to integrate immunotherapy with radiation, either at the same time or sequentially, to evaluate safety and therapeutic potential.

Evidence from Clinical Trials: Potential Benefits and Known Risks

In the phase II BTCRC-GU15-023 trial, patients who were not eligible for surgery or cisplatin-based chemotherapy received radiation in combination with the PD-L1 inhibitor durvalumab. The majority experienced disease control, with over half achieving a complete response. Progression-free survival extended beyond 21 months, and the treatment was generally well-tolerated.

The ANZUP trial, conducted in Australia, tested a combination of pembrolizumab with chemoradiation in patients who opted for bladder preservation or were medically ineligible for surgery. The results showed an 88% complete response rate at 24 weeks. However, serious adverse events occurred in approximately one-third of patients, including a treatment-related death.

INTACT, an ongoing trial, is also investigating whether adding immunotherapy to standard bladder-preserving treatment—combining surgery, chemotherapy, and radiation—can improve outcomes for patients with advanced bladder cancer.

The review also highlights other studies where treatment combinations led to unacceptable toxicity, especially when high-dose radiation was paired with multiple immune-modulating drugs. These findings emphasize the importance of careful dosing and patient monitoring.

Mechanistic Insights: How the Combination Works

Radiation alters the tumor microenvironment by releasing tumor proteins and pro-inflammatory signals. This can increase the inflammation, infiltration and activity of immune cells. Immunotherapy boosts this process by reactivating suppressed T-cells, potentially leading to systemic responses beyond the targeted tumor site—a phenomenon known as the abscopal effect. The review also notes preclinical data suggesting that radiation may enhance tumor visibility and reverse immune evasion.

Implications for Treatment Planning

The review suggests that this combination strategy, radiation and immunotherapy, may be particularly relevant for patients who are not candidates for surgery or traditional chemotherapy. It may also expand the role of bladder-preserving approaches for advanced bladder cancer. However, variability in patient response and the risk of compounded toxicities remain barriers to broader clinical application.

Future Perspectives and Conclusion

While current findings point to potential benefits, the review emphasizes that additional studies are needed before this combined treatment can become standard clinical practice. A major focus moving forward will be identifying which patients are most likely to benefit—possibly through biomarkers such as tumor mutation burden or immune infiltration levels—and refining treatment combinations to reduce toxicity.

By examining the interaction between radiation and immunotherapy, this review contributes meaningfully to ongoing efforts aimed at developing more personalized and effective therapeutic strategies in bladder cancer.

Click here to read the full review in Oncotarget.

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

January 28, 2025

“The anti-correlation of PD-1 and KLRG1 expression in human tumor infiltrating CD8 T cells suggests the potential for combination therapy supra-additive benefits of anti-PD-1 and anti-KLRG1 therapies.”

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.

The Challenge: Overcoming Limitations of PD-1 Immunotherapy

PD-1 inhibitors have transformed cancer treatment by enabling the immune system to fight back. However, these therapies have notable limitations. Some patients do not respond to treatment, and many experience only moderate or short-term benefits. Even combining PD-1 inhibitors with other therapies often provides only additive effects rather than true synergy, where the combined treatment outperforms the sum of its parts. This has left researchers searching for combinations that could deliver “supra-additive” effects.

Results: The Surprising Anti-Correlation Between KLRG1 and PD-1

One protein, KLRG1, stood out. This checkpoint receptor has received little attention in cancer research. Historically, it was thought to merely mark aging, or “senescent,” T cells—cells that are no longer active. However, Dr. Greenberg’s research revealed that KLRG1 plays a more dynamic role in regulating immune responses, challenging its previously underestimated significance.

The study found that in tumor-infiltrating CD8 T cells, which are crucial in the immune system’s fight against cancer, the levels of PD-1 and KLRG1 move in opposite directions. As these T cells mature and become more effective at killing cancer cells, they show an increase in KLRG1 expression while PD-1 levels decrease. This pattern of anti-correlation was consistently observed across the different types of cancer.

The Breakthrough: A New Approach to Combination Therapy

Unlike conventional combination strategies, which often target multiple positively correlated exhaustion markers (such as PD-1, TIM-3, and LAG-3), targeting the negatively correlated KLRG1 introduces a fresh approach.

KLRG1-positive T cells are highly differentiated and effective at destroying cancer cells, while PD-1-positive cells are in a more ‘exhausted’ state. Combining treatments to target both populations could achieve true synergy, offering a promising solution to the limitations of current immunotherapy.

The Potential for Cancer Patients

If future research confirms the therapeutic potential of targeting KLRG1, this could revolutionize cancer immunotherapy. Patients who do not respond well to PD-1 inhibitors alone might benefit from adding KLRG1-targeting therapies, offering a lifeline for those with limited options.

This approach also holds promise for treating difficult cancers like lung cancer and melanoma. By tailoring treatments to individual immune profiles, clinicians could deliver personalized and precise immunotherapy, improving outcomes and reducing the risk of cancer recurrence.

Combining KLRG1 with PD-1 inhibitors could provide cancer patients with renewed hope, leading to improved health and extended survival.

Conclusion and Future Directions

The discovery of the relationship between KLRG1 and PD-1 provides an exciting new avenue for cancer treatment. By addressing the limitations of current immunotherapies, this approach has the potential to deliver more effective and longer-lasting treatments.

The next steps will include preclinical studies and clinical trials to evaluate the safety and effectiveness of combining KLRG1-targeting therapies with PD-1 inhibitors. If successful, this approach could transform cancer immunotherapy and offer hope to millions of patients worldwide.

Click here to read the full research paper in Oncotarget.

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CDR3s and Renalase-1 Correlate with Increased Melanoma Survival

September 26, 2024

“Our group has demonstrated that chemical complementarity between tumor resident, T-cell receptor, complementarity-determining region 3 (CDR3s), and MAGEA3/6 correlates with increased survival in patients with melanoma.”

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In this study, Saif Zaman, Fred S. Gorelick, Andrea Chrobrutskiy, Boris I. Chobrutskiy, Gary V. Desir, and George Blanck from Yale School of Medicine, Veteran’s Administration Healthcare System, Oregon Health and Science University Hospital, Morsani College of Medicine, and the H. Lee Moffitt Cancer Center and Research Institute, investigated the chemical complementarity between melanoma-resident T-cell receptor (TCR) complementarity-determining region 3 (CDR3) amino acid sequences (AAs) and the renalase-1 protein. On August 5, 2024, their research paper was published in Oncotarget ‘s Volume 15, entitled, “Chemical complementarity of tumor resident, T-cell receptor CDR3s and renalase-1 correlates with increased melanoma survival.”

The Study

The researchers investigated the potential of the RP220 peptide as an antigenic target for T cells by assessing the electrostatic and hydrophobic complementarity between T-cell receptor (TCR) CDR3s and the RP220 peptide of the renalase (RNLS) protein. They found that higher complementarity scores were linked to significantly improved survival probabilities, with hydrophobic forces further refining these distinctions. The associations varied depending on the dataset and method used.

The study also explored correlations between TCR CDR3-RNLS amino acid alignments and immune gene expression. Several immune signature genes, such as CD86, TIGIT, CIITA, and CD4, were significantly associated with better overall survival when showing higher complementarity scores.

Researchers also examined how RNLS expression levels affected these correlations. They found that higher RNLS mRNA expression was associated with worse survival, while lower RNLS expression combined with high complementarity scores predicted better outcomes. This trend held for both the full-length RNLS protein and the RP220 peptide.

The study revealed that specific regions of the RNLS protein, including the RP220 peptide, had higher complementarity with TCR CDR3s, suggesting they may serve as potential antigenic targets.

Discussion

The researchers explored the potential of the RNLS protein as a tumor antigen by examining the chemical complementarity between melanoma tumor-resident T-cell receptor (TCR) CDR3s and the amino acid (AA) sequence of RNLS. They found that increasing complementarity correlated with improved overall survival (OS) outcomes, supporting previous in vitro and in vivo data. This suggests that RNLS could be recognized by TCRs, triggering immune responses against melanoma.

Gene expression analyses revealed that as complementarity scores between TCRs and RNLS AAs increased, so did the expression of T-cell activation-associated genes, indicating enhanced T-cell activity and anti-tumor immune responses. The association between TCR complementarity and OS probabilities was more pronounced in cases with low RNLS expression levels, suggesting that high complementarity may be particularly beneficial in tumors with reduced RNLS-mediated immune inhibition.

These findings suggest that RNLS could serve as an antigen for TCRs in melanoma, supporting further exploration of its potential as a target for immunotherapy and vaccine design.

In conclusion, this research suggests that RNLS could potentially serve as an antigen for T-cell receptors (TCRs) in melanoma. The correlation between TCR complementarity to RNLS and improved overall survival supports the idea that T-cell responses targeting RNLS may play a role in antitumor immunity. These findings highlight the potential of RNLS as a valuable target for immunotherapy and vaccine development for melanoma treatment.

Further research in this area is warranted.

Click here to read the full research paper in Oncotarget.

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Impact of Dual Immunotherapies Before Surgery in HR+/HER2-negative Breast Cancer

June 20, 2024

In this new study, researchers assessed the feasibility of treating HR+/HER2-negative breast cancer patients with the immunotherapies durvalumab and tremelimumab before standard neoadjuvant chemotherapy and surgery.

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Breast cancer immunotherapy has shown promise, but its clinical efficacy remains limited, especially for hormone receptor positive (HR+)/HER2-negative breast cancer. While immune checkpoint inhibitors combined with chemotherapy have benefitted some early-stage and metastatic triple-negative breast cancer patients, HR+/HER2-negative cases have seen fewer improvements.

Recent neoadjuvant trials indicate that early-stage HR+/HER2-negative breast cancers might respond better to immunotherapy strategies that amplify tumor-infiltrating lymphocytes (TILs) through dual PD-(L)1/CTLA-4 checkpoint inhibition before surgery and chemotherapy. This approach could enhance the immune response in the tumor microenvironment and improve outcomes for this challenging breast cancer subtype.

The Study

Increased TILs are associated with improved neoadjuvant chemotherapy (NACT) responses across breast cancer subtypes. Recently, researchers Haven R. Garber, Sreyashi Basu, Sonali Jindal, Zhong He, Khoi Chu, Akshara Singareeka Raghavendra, Clinton Yam, Lumarie Santiago, Beatriz E. Adrada, Padmanee Sharma, Elizabeth A. Mittendorf, and Jennifer K. Litton from the University of Texas MD Anderson Cancer Center, Brigham and Women’s Hospital, Dana-Farber Brigham Cancer Center, and Harvard Medical School hypothesized that amplifying TILs via dual checkpoint blockade would enhance the response to subsequent NACT in breast tumors.

Their new study aimed to assess the feasibility of enrolling untreated patients with stage II or III HR+/HER2-negative breast cancer for upfront treatment with combined PD-L1/CTLA-4 checkpoint inhibition before standard NACT and surgery. The research paper, published in Oncotarget’s Volume 15 on March 19, 2024, was entitled, “Durvalumab and tremelimumab before surgery in patients with hormone receptor positive, HER2-negative stage II–III breast cancer.”

“This feasibility study was conducted to begin testing the hypothesis that dual checkpoint blockade would increase TIL and enhance the response to subsequent NACT in patients with stage II or III HR+/HER2-negative breast cancer.”

Patient Screening, Recruitment, & Assessment

The study aimed to accrue 16 patients to evaluate the feasibility of enrolling patients with clinical stage II or III HR+/HER2-negative breast cancer onto a trial evaluating investigational immunotherapy agents before standard NACT. Patient tumor samples were collected to assess immunologic and molecular responses to combination checkpoint blockade.

Eligible patients had to have HR+/HER2-negative breast cancer, defined as estrogen receptor (ER) and/or progesterone receptor (PR) expression >10% by immunohistochemistry (IHC), and HER2-negative defined as 0/1+ by IHC or if 2+, negative by fluorescence in situ hybridization. Other inclusion criteria included an ECOG performance status of 0 or 1, planned NACT, and adequate blood counts and organ function.

Patients were excluded if they had received prior PD-1, PD-L1, or CTLA-4 inhibitors or any prior treatment for the primary breast cancer. Other exclusions included current or prior use of immunosuppressive medications within 28 days, active or previous autoimmune disease within 2 years, inflammatory bowel disease, or receipt of a live attenuated vaccination within 30 days before study entry or treatment.

Durvalumab was administered at 1500 mg IV, and tremelimumab at 75 mg IV for 2 cycles on days 1 and 28. Patients then proceeded to standard NACT followed by breast surgery. Baseline breast ultrasounds were performed within 21 days before the first immunotherapy cycle and again between 1 and 7 days after the second cycle. Research biopsies were collected at baseline and after 2 cycles of immunotherapy.

Results & Discussion

The trial’s target accrual of 16 patients was not met, as it was stopped early after three of the first eight enrolled patients experienced immunotherapy-related toxicity or suspected disease progression, indicating that this strategy is not clinically feasible.

Among the eight patients who did receive the study-specified combination immunotherapy, seven had pre- and post-immunotherapy ultrasounds performed, showing mixed responses. Three experienced an increase in tumor volume, three a decrease, and one showed stable disease. The impact of combination immunotherapy on TILs was also mixed. Though limited by the number of patients with available serial biopsies, there did not appear to be a significant increase in the immune response within the tumor microenvironment (TME).

The Phase II NIMBUS trial also assessed dual checkpoint blockade in breast cancer, though in a population of metastatic breast cancer patients with tumors harboring a high tumor mutation burden (TMB ≥9 mutations per megabase). Of the 30 patients enrolled, 20 had ER+/HER2-negative breast cancer. The overall response rate (ORR) was 16.7%, with four durable responses lasting at least 15 months. Three of the five responders had a TMB ≥14 mutations per megabase. The ORR among patients with TMB <14 mutations per megabase was 6.7%. Three patients (10%) experienced grade 3 immune toxicity.

The TAPUR basket trial similarly included patients with TMB-high metastatic breast cancer but utilized single-agent anti-PD-1 checkpoint blockade (pembrolizumab) rather than combination immunotherapy. Half of the 28 enrolled patients had ER+ breast cancer, and the majority had received multiple prior lines of systemic therapy. The ORR was 21% with a median progression-free survival (PFS) of 10.6 weeks. Five patients (17.9%) experienced one or more grade 3 adverse events possibly attributed to pembrolizumab, and six patients discontinued treatment due to side effects.

In summary, while a minority of patients with ER+ metastatic breast cancer may benefit from anti-PD-(L)1/anti-CTLA-4 checkpoint blockade, the majority risk exposure to immune-related adverse events without additional benefit.

Conclusion & Future Directions

The present study did not demonstrate a clear benefit for dual checkpoint blockade administered prior to NACT in patients with stage II or III HR+/HER2-negative breast cancer. Only one out of eight patients (12.5%) achieved a pathologic complete response (pCR) at the time of breast surgery after immune therapy and NACT. Two patients experienced grade 3 immunotherapy-related toxicity.

While the KEYNOTE-756 and CheckMate 7FL trials have demonstrated improved pCR rates with the addition of single-agent anti-PD-1 checkpoint blockade to NACT for patients with high-risk HR+/HER2-negative, stage II/III breast cancer, the risk/benefit calculus of adding immunotherapy for this subtype is different from metastatic triple-negative breast cancer (TNBC) or even stage II/III TNBC, where the risks of morbidity and mortality from disease are higher.

Hopefully, biomarkers such as PD-L1 expression and tumor mutation burden (TMB) will guide the use of single or dual-agent immunotherapy towards those patients most likely to benefit, sparing others from significant toxicity. Notably, immune-mediated adverse events of grade 3 or higher were reported in 12.9% of breast cancer patients receiving pembrolizumab in the KEYNOTE-522 trial and in 38% of patients receiving dual ipilimumab/nivolumab in a trial of patients with metastatic melanoma.

For immunotherapy to play a meaningful role in HR+/HER2-negative early breast cancer, a breast cancer subtype where most patients are cured with standard therapy, it will need to significantly increase the fraction of cured patients without disproportionately causing serious and/or long-term immune toxicity. Future research should focus on identifying predictive biomarkers and optimizing combination strategies to enhance the efficacy of immunotherapy in this challenging breast cancer subtype.

Click here to read the full research paper in Oncotarget.

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Immunotherapy Response in Primary vs Metastatic Pancreatic Cancer

November 16, 2023

In this editorial, researchers delve into the immunotherapeutic challenges posed by the tumor microenvironment and liver metastasis in pancreatic cancer.

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Pancreatic ductal adenocarcinoma (PDA), a common type of pancreatic cancer, has proven to be largely resistant to immunotherapy, a treatment that uses the body’s immune system to fight cancer. Despite numerous successful pre-clinical trials using sophisticated PDA mouse models, clinical trials have failed to show a significant improvement in survival.

In a recent editorial, researchers Brian Diskin, Sarah Schwartz and George Miller from Trinity Health of New England shed light on the complex interplay between the immune system and pancreatic cancer. Their paper was published in Oncotarget on April 24, 2023, and entitled, “The critical immune basis for differential responses to immunotherapy in primary versus metastatic pancreatic cancer.”

Tumor Microenvironment and Liver Metastasis: Challenges in Pancreatic Cancer

The authors attribute PDA immunotherapy resistance to the unique characteristics of the tumor microenvironment (TME). The TME is often hypoxic and fibrotic, making it inaccessible to immune cells. Furthermore, the immune cells that do infiltrate the TME often have tolerogenic features, meaning they are more likely to tolerate the presence of cancer cells rather than attack them.

PDA most commonly metastasizes to the liver, an organ known for its immune tolerance. The liver is home to a diverse array of innate immune populations, including NK cells, Kupfer cells, NKT cells, and double negative T cells. Despite this, the liver is the most common location for metastasis from gastrointestinal cancers.

“It is an unfortunate fact that all failed clinical trials assessing immunotherapeutic efficacy were conducted in metastatic PDA, whereas basic preclinical investigations are usually performed in primary PDA using genetically engineered mouse models. We postulated that this dichotomy may explain the gap between preclinical promise and ultimate clinical failure.”

Divergent Responses to Immunotherapy: Primary vs. Metastatic

“The potentially divergent responses to immunotherapy in the respective environments of primary versus metastatic PDA within the same host has not been well-studied.”

The authors highlight the lack of research into the potentially divergent responses to immunotherapy in primary versus metastatic PDA. They argue that this gap in knowledge may explain the discrepancy between the promising results of pre-clinical trials and the disappointing outcomes of clinical trials.

In their research, they discovered that the TMEs of primary PDA and liver metastases differ significantly, and this difference plays a critical role in the site-specific response to immunotherapy. They found that liver metastases are uniquely resistant to immunotherapies, in stark contrast to the immunotherapeutic responsiveness of primary PDA.

“We discovered that the respective TMEs of primary PDA and liver metastases differ markedly and this fact plays a critical role in dictating site-specific PDA response to immunotherapy [6].”

The Role of B Cells

The researchers identified B cells as a key player in this differential response. They found that B cells constituted approximately 25% of the tumor-infiltrating lymphocytes in metastatic PDA liver deposits, compared to approximately 10% in primary PDA. They also discovered a novel population of CD24+CD44–CD40– B cells in the metastatic liver, which is recruited to the metastatic milieu by Muc1hiIL18hi tumor cells.

“[…] by targeting B cells or blocking CD200/BTLA, we demonstrated enhanced macrophage and T-cell immunogenicity, which enabled immunotherapeutic efficacy of liver metastases.”

However, the authors note that primary PDA sites lack this b-cell population. Instead, they are characterized by macrophages and effector T cells that have a higher ability to provoke an immune response. This makes their immunotherapeutic responsiveness far more robust than metastatic liver PDA.

Conclusion

This research underscores the importance of understanding the immune basis of differential responses to immunotherapy in primary versus metastatic pancreatic cancer. It highlights the need for further research into the role of the TME and immune cells like B cells in the response to immunotherapy. Such insights could pave the way for more effective treatments for this challenging disease.

“[…] our data suggest that models of primary PDA are poor surrogates for evaluating immunity or treatment response in advanced disease.”

Click here to read the full editorial paper in Oncotarget.

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Oncotarget

Epigenetics and Immunotherapy Combined Fights Rare Lymphoma

August 24, 2022

In a new Oncotarget study, researchers assessed an epigenetic and immunotherapy treatment regimen among patients with blastic mantle cell lymphoma (bMCL).

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Mantle cell lymphoma (MCL) is a type of non-Hodgkin’s lymphoma (NHL) that is aggressive, difficult to treat and typically affects older adults. Recurrence and mortality rates among patients with MCL have remained high, despite recent therapeutic advances. Blastic mantle cell lymphoma (bMCL) is a rare subtype of MCL associated with a worse disease trajectory.

“Despite recent advances, MCL is incurable except with allogeneic stem cell transplant. Blastic mantle cell lymphoma (bMCL) is a rarer subtype of cMCL associated with an aggressive clinical course and poor treatment response, frequent relapse and poor outcomes.”

In previous studies, researchers reported that a combination of epigenetic and immunotherapy treatments may have synergistic activity and offer better outcomes in patients with MCL. In the current study, Francis R. LeBlanc, Zainul S. Hasanali, August Stuart, Sara Shimko, Kamal Sharma, Violetta V. Leshchenko, Samir Parekh, Haiqing Fu, Ya Zhang, Melvenia M. Martin, Mark Kester, Todd Fox, Jiangang Liao, Thomas P. Loughran, Juanita Evans, Jeffrey J. Pu, Stephen E. Spurgeon, Mirit I. Aladjem, and Elliot M. Epner from Pennsylvania State University College of Medicine, Penn State Hershey Cancer Institute, Winter Haven Hospital Cassidy Cancer Center, Icahn School of Medicine at Mount Sinai, National Cancer Institute, University of Virginia, UVA Cancer Center, University of Arizona College of Medicine, Oregon Health and Science University, and Beverly Hills Cancer Center used samples from a previous trial to perform correlative studies focused on clinical results in patients with blastic MCL. On August 16, 2022, their research paper was published in Volume 13 of Oncotarget, entitled, “Combined epigenetic and immunotherapy for blastic and classical mantle cell lymphoma.”

Epigenetic and Immunotherapy

Epigenetic therapy includes a range of drugs that can target epigenetic mechanisms, including DNA methylation and posttranslational modifications of histones. For example, vorinostat (SAHA; a histone deacetylase inhibitor) and cladribine (chemotherapy that also inhibits DNA methylation) are epigenetic agents. Rituximab, a maintenance immunotherapeutic agent, is a CD20-directed monoclonal antibody. These three treatments combined encompass a novel potential epigenetic and immunotherapy treatment regimen (SCR) for mantle cell lymphoma (MCL).

“Relapsed and [treatment] naïve MCL patients were treated with vorinostat (SAHA), cladribine and rituximab (SCR) regimen and followed for OS [overall survival], progression free survival (PFS) and with correlative basic science studies to investigate potential mechanisms of action of this epigenetic/immunotherapy combination.”

The Study

Since blastic MCL patients are rare, only 13 bMCL (four relapsed, nine previously untreated) patients treated with the SCR regimen were assessed in the prospective part of this study. All patients were male and Caucasian, and the median age at diagnosis was 62 years old. The patients were treated until they achieved remission, met the criteria for removal from the study, withdrew from the study, or passed away. Four patients were changed from rituximab to ofatumumab (a potent fully-human anti-CD20 antibody) due to rituximab intolerance (allergies, reactions) or lack of efficacy.

“Of 13 bMCL patients, all patients responded to therapy, with 12 patients meeting criteria for remission (CR, n = 6; PR, n = 6). Of those achieving CR, 5 remain in CR more than 5 years after diagnosis.”

Results

After a median of 4.8 cycles of therapy, 12 patients achieved a complete response (CR), and one patient maintained stable disease (SD). The patients reported an increased overall survival greater than 40 months, and several patients maintained durable remissions without relapse for longer than five years. These results are remarkably superior to current treatment regimens with conventional chemotherapy, which range from 14.5-24 months among bMCL patients.

“The median OS of 43.4 months and PFS of 17.3 months for MCL patients with blastic disease treated with SCR therapy is one of the most important outcomes in this study.”

Another important finding was that the G/A870 CCND1 polymorphism was a strong predictor of blastic MCL, nuclear localization of cyclinD1 and response to SCR therapy. The team identified two distinct mechanisms of resistance to SCR therapy. The researchers reported that the loss of CD20 expression and evading treatment by seeking sanctuary in the central nervous system were two major resistance mechanisms to SCR therapy.

“These data indicate that administration of epigenetic agents improves efficacy of anti-CD20 immunotherapies.”

Conclusion

Although the study sample was relatively small, the researchers’ results are promising. The SCR regimen was demonstrated to be an effective epigenetic and immunotherapy treatment for mantle cell lymphoma, with long-term remissions and improved overall survival in bMCL patients. Researchers revealed important insights into the mechanisms of action of SCR and potential resistance mechanisms. This study also highlights the potential for future research exploring the efficacy of SCR in other cancers, along with other predictive biomarkers of response.

“This approach is promising in the treatment of MCL and potentially other previously treatment refractory cancers.”

Click here to read the full research paper published by Oncotarget.

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