Neoadjuvant botensilimab plus balstilimab response pattern in locally advanced mismatch repair proficient colorectal cancer

Kasi, Pashtoon Murtaza; Hidalgo, Manuel; Jafari, Mehraneh D.; Yeo, Heather; Lowenfeld, Lea; Khan, Uqba; Nguyen, Alana T. H.; Siolas, Despina; Swed, Brandon; Hyun, Jini; Khan, Sahrish; Wood, Madeleine; Samstein, Benjamin; Rocca, Juan P.; Ocean, Allyson J.; Popa, Elizabeta C.; Hunt, Daniel H.; Uppal, Nikhil P.; Garrett, Kelly A.; Pigazzi, Alessio; Zhou, Xi Kathy; Shah, Manish A.; Hissong, Erika

doi:10.1038/s41388-023-02835-y

Cited by 10 publications

(6 citation statements)

References 15 publications

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“…However, a recent clinical trial shows that a significant proportion (about 30%) of early-stage pMMR/MSS CRCs have pathological responses (PRs) to a combination of ipilimumab and nivolumab in the neoadjuvant setting [ 39 , 40 ]. Furthermore, recent phase 2 clinical trials exploring combination therapies, such as anti-CTLA-4 plus anti-PD-1 or anti-PD1 plus the HDAC inhibitors chidamide alongside bevacizumab, have produced promising efficacy with manageable toxicity in pMMR/MSS mCRCs [ 41 , 42 ]. Together, these results support the potential effectiveness of immunotherapy as a viable treatment choice for pMMR/MSS mCRCs in the near future.…”

Section: Discussionmentioning

confidence: 99%

Enhanced abscopal anti-tumor response via a triple combination of thermal ablation, IL-21, and PD-1 inhibition therapy

Wu,

Jiang,

Fang

et al. 2024

Cancer Immunol Immunother

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Despite the success of immune checkpoint inhibitors (ICIs) in treating solid tumors, lots of patients remain unresponsive to this therapy. Microwave ablation (MWA) stimulates systemic adaptive immunity against tumor cells by releasing tumor antigens. Additionally, IL-21 has demonstrated importance in stimulating T-cell effector function. The combination of these three therapies—MWA, IL-21, and anti-PD-1 monoclonal antibodies (mAbs)—has yet to be explored in the context of cancer treatment.In this study, we explored the impact of thermal ablation on IL-21R expression in tumor-infiltrating lymphocytes (TILs). Subsequently, we assessed alterations in the tumor microenvironment (TME) and peripheral lymphoid organs. Additionally, we conducted a thorough examination of tumor-infiltrating CD45+ immune cells across various treatment groups using single-cell RNA sequencing (scRNA-seq). Moreover, we determined the potential anti-tumor effects of the triple combination involving MWA, IL-21, and anti-PD-1 mAbs.Our findings revealed that MWA upregulated the expression of IL-21R on various immune cells in the untreated tumors. The combination of MWA with IL-21 exhibited a robust abscopal anti-tumor effect, enhancing the effector function of CD8+ T cells and facilitating dendritic cells' maturation and antigen presentation in the untreated tumor. Notably, the observed abscopal anti-tumor effect resulting from the combination is contingent upon T-cell recirculation, indicating the reliance of systemic adaptive immunity for this treatment regimen. Additionally, the combination of MWA, IL-21, and PD-1 mAbs demonstrated profound abscopal anti-tumor efficacy. Our findings provide support for further clinical investigation into a triple combination therapy involving MWA, IL-21, and ICIs for the treatment of metastatic cancer.

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Section: Discussionmentioning

confidence: 99%

Enhanced abscopal anti-tumor response via a triple combination of thermal ablation, IL-21, and PD-1 inhibition therapy

Wu,

Jiang,

Fang

et al. 2024

Cancer Immunol Immunother

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“…Like NICHE, this trial administers one dose of the anti-CTLA-4 antibody and two doses of the anti-PD-1 antibody before surgery. A report of dramatic pathologic response in two patients with pMMR cancer on this trial has been reported [ 16 ]. Of note was the finding of a massive immune infiltrate in these cancers resulting in residual viable tumor only near the luminal surface of the colon.…”

Section: Neoadjuvant Therapy For Pmmr Laccmentioning

confidence: 99%

“…Neoadjuvant immunotherapy is of great interest for patients with deficient mismatch repair (dMMR) LACC given the remarkable pathologic and clinical responses reported in trials of dMMR LACC and rectal cancer [ 12 ••, 13 – 15 ]. Most patients with LACC have proficient mismatch repair (pMMR) disease, and there is great interest in extending the potentially curative benefits of immunotherapy to this large population in the neoadjuvant setting [ 12 ••, 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Preoperative Strategies for Locally Advanced Colon Cancer

Nair,

Kamath,

Chowattukunnel

et al. 2024

Curr. Treat. Options in Oncol.

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Opinion statementNeoadjuvant chemotherapy is safe for patients with locally advanced colon cancer (LACC). The FOxTROT trial demonstrated a reduction in residual and recurrent cancer at 2 years with neoadjuvant chemotherapy for patients with cT3-4 LACC. Preoperative chemotherapy should be avoided, if possible, for patients with dMMR LACC, as over 50% of dMMR cancers have no pathologic response. Early universal testing of MMR status is critical to selecting the appropriate neoadjuvant therapy. Concerns about CT staging of LACC have limited uptake of neoadjuvant chemotherapy, as approximately 25% of patients with cT3-T4 cancer on CT have low-risk stage II disease. Development of CT criteria for malignant nodes should reduce the risk of over-staging. A multidisciplinary approach is needed to identify patients for neoadjuvant therapy. Neoadjuvant immunotherapy is safe and results in dramatic pathologic responses in patients with dMMR LACC. Longer follow-up is needed to determine if the exceptionally high pathologic response rates observed will translate into long-term remission. Remarkably, neoadjuvant immunotherapy has been found to cause major pathologic responses in a subset of patients with pMMR LACC, indicating the potential to cure more patients with this common cancer. Patients with cT4 LACC, whether stage II or III, have a substantial risk of recurrence despite adjuvant fluoropyrimidine plus oxaliplatin chemotherapy. We recommend neoadjuvant systemic therapy for all patients with cT4b LACC (dMMR and pMMR). Features of T4b disease are routinely reported by radiology. We use three cycles of FOLFOX chemotherapy for patients with cT4b pMMR LACC, due to the high rate of compliance and improvement in residual and recurrent disease. Patients with cT4b dMMR LACC should receive neoadjuvant immunotherapy, if there are no contraindications. Clinical trials of neoadjuvant therapy for LACC are of great interest and should provide training for radiologists to identify eligible patients. Results are anticipated from multiple ongoing trials of neoadjuvant chemotherapy, immunotherapy, and targeted therapy for pMMR LACC and immunotherapy for dMMR LACC.

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“…Novel potential agents are on the way. Some interesting signals of efficacy have been detected in patients treated with the combination of Botensilimab, a novel anti-CTLA-4 antibody, and Balstilimab, a next-generation PD-1 inhibitor [47]. This promising therapeutic strategy has already provided interesting results in the metastatic setting [48] and is currently under investigation in patients with LARC.…”

Section: Mismatch Repair-proficient (Pmmr) or Microsatellite Stabilit...mentioning

confidence: 99%

Advancing Personalized Medicine in the Treatment of Locally Advanced Rectal Cancer

Sullo,

Passardi,

Gallio

et al. 2024

JCM

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Rectal cancer presents a significant burden globally, often requiring multimodal therapy for locally advanced cases. Long-course chemoradiotherapy (LCRT) and short-course radiotherapy (SCRT) followed by surgery have been conventional neoadjuvant approaches. Recent trials favor LCRT due to improved local control. However, distant tumor recurrence remains a concern, prompting the exploration of total neoadjuvant therapy (TNT) as a comprehensive treatment strategy. Immune checkpoint inhibitors (ICIs) show promise, particularly in mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors, potentially revolutionizing neoadjuvant regimens. Nonoperative management (NOM) represents a viable alternative post-neoadjuvant therapy for selected patients achieving complete clinical response (cCR). Additionally, monitoring minimal residual disease (MRD) using circulating tumor DNA (ctDNA) emerges as a non-invasive method for the assessment of treatment response. This review synthesizes current evidence on TNT, ICIs, NOM, and ctDNA, elucidating their implications for rectal cancer management and highlighting avenues for future research and clinical application.

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Neoadjuvant botensilimab plus balstilimab response pattern in locally advanced mismatch repair proficient colorectal cancer

Cited by 10 publications

References 15 publications

Enhanced abscopal anti-tumor response via a triple combination of thermal ablation, IL-21, and PD-1 inhibition therapy

Enhanced abscopal anti-tumor response via a triple combination of thermal ablation, IL-21, and PD-1 inhibition therapy

Preoperative Strategies for Locally Advanced Colon Cancer

Advancing Personalized Medicine in the Treatment of Locally Advanced Rectal Cancer

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