Tagged: immunotherapy

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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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.

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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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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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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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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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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