International Journal of Clinical Oncology最新文献

Despite multimodal treatment options, most gastrointestinal (GI) cancers remain associated with high mortality rates and poor responsiveness to immunotherapy. The remarkable success of immune cell-based therapies in hematologic malignancies has raised interest in translating adoptive cell therapies to GI cancers. Among these approaches, natural killer (NK) cell-based therapies offer potent cytotoxicity, and a favorable safety profile. Multiple NK cell platforms are now under preclinical and clinical development, demonstrating encouraging therapeutic efficacy in GI malignancies. Nevertheless, challenges such as limited in vivo persistence, immunosuppressive tumor microenvironment (TME), and heterogeneous expression of NK cell therapy targeted antigens continue to limit therapeutic benefit. Recent advances are being explored to overcome these barriers and enhance NK cell persistence and specificity. This review summarizes recent progress in NK cell-based immunotherapy for GI cancers, highlights representative clinical trials, and discusses strategies to improve efficacy and durability. With continued innovation, NK cell-based therapy holds promise to become an essential component of the future immunotherapy landscape for GI malignancies.

Background: JO40295 (jRCT2080223801) evaluated the efficacy and safety of subcutaneous (SC) mosunetuzumab, in combination with lenalidomide and as monotherapy, in Japanese patients with relapsed/refractory (R/R) follicular lymphoma (FL). We report outcomes from the interim analysis of the FLMOON-2 (≥ 1 prior therapy; mosunetuzumab plus lenalidomide) and primary analysis of the FLMOON-3 (≥ 2 prior therapies; mosunetuzumab monotherapy) cohorts.

Methods: Mosunetuzumab SC was administered with Cycle (C)1 step-up dosing in both cohorts: C1 Day (D)1, 5 mg; C1D8, D15 and C2 onwards, 45 mg. In FLMOON-2, oral lenalidomide was administered from C2 onwards, on D1-21 of each cycle. Treatment was administered up to C12 in FLMOON-2 and C8 or C17 in FLMOON-3. The primary endpoint was independent review facility-assessed complete response (CR) rate.

Results: At the clinical cut-off date (FLMOON-2: April 4, 2024; FLMOON-3: March 4, 2024), in the efficacy-evaluable populations, CR rate was 92.3% in FLMOON-2 (n = 13) and 100% in FLMOON-3 (n = 5). In the safety-evaluable populations (FLMOON-2, n = 17; FLMOON-3, n = 5), Grade 3/4 adverse events (AEs) occurred in 64.7% of patients in FLMOON-2 and 20.0% in FLMOON-3. No Grade 5 AEs or AEs leading to treatment discontinuation occurred in either cohort. Cytokine release syndrome was reported in 47.1% of patients in FLMOON-2 and 20.0% in FLMOON-3. Serum mosunetuzumab concentration peaked with the third dose of mosunetuzumab in C1 and reached a steady state with repeated dosing.

Conclusion: Mosunetuzumab SC, in combination with lenalidomide and as monotherapy, demonstrated promising efficacy with a manageable safety profile in Japanese patients with R/R FL.

Background: Lisocabtagene maraleucel (liso-cel), an anti-CD19 CAR T cell therapy, has demonstrated efficacy in relapsed/refractory (R/R) large B cell lymphoma (LBCL). However, real-world data from commercial settings outside the United States remain limited.

Methods: To evaluate the safety and effectiveness of commercial-use liso-cel in Japan, we conducted a single-center retrospective study of patients with R/R LBCL who received commercial-use liso-cel at our institution between November 2021 and November 2024.

Results: 56 patients received liso-cel infusion. The median age was 66.5 years, and 55.4% had primary refractory disease. Liso-cel was administered as second-line therapy in 14 patients (25.0%) and as third-line or later therapy in 42 patients (75.0%). The best overall response rate was 80.4%, with a complete response rate of 78.6%. At a median follow-up of 12.3 months, 1 year progression-free survival (PFS) and overall survival rates were 69.5% and 86.4%, respectively. The 1 year PFS rates were 68.5% for diffuse large B cell lymphoma not otherwise specified, 100% for primary mediastinal large B cell lymphoma (PMBCL), and 30% for high-grade B cell lymphoma (HGBCL). Grade ≥ 3 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome were observed in one patient each. Multivariate analysis identified HGBCL subtype and higher pre-infusion metabolic tumor volume as independent adverse factors for PFS.

Conclusion: Commercial-use liso-cel demonstrated high response rates and favorable safety in Japanese patients with R/R LBCL. Patients with PMBCL had excellent outcomes, whereas those with HGBCL showed poorer prognosis, indicating a need for further therapeutic strategies.

Background: Although human papillomavirus (HPV) vaccines effectively prevent cervical cancer, the HPV vaccination rates in Japan remain low because of concerns about alleged neurological adverse events. Darja Kanduc proposed a flawed hypothesis that molecular mimicry between HPV and human proteins could induce cross-reactive antibodies, causing autoimmune organ damage, even when only the portions of amino acid (AA)-sequences of the epitopes were identical between HPV and human proteins.

Methods: In this study, we conducted the same computational data analysis as Kanduc, using 22 linear epitopes (9-23 AA-length) of the HPV type 16 L1 protein (HPV16L1) registered in the database.

Results: We found that no human epitopes had identical AA-sequences to any HPV16L1 epitopes, demonstrating that HPV16L1 had no molecular mimicry with linear epitopes that have the potential to induce cross-reactive autoantibodies. On the other hand, we identified various numbers of human protein epitopes whose AA-sequences were partially identical with epitopes of HPV16L1, hepatitis B virus (HBV), and respiratory syncytial virus (RSV). We found that HPV16L1 had a smaller number of such proteins having "partial molecular mimicry" than HBV and RSV.

Conclusions: Our current in silico analysis provided no evidence that HPV vaccinations could induce cross-reactive autoantibodies. The flawed molecular mimicry data should not be used as a scientific basis for alleged HPV vaccine-induced adverse events.

Objective: To evaluate the real-world safety and efficacy of immune checkpoint inhibitors (ICIs) in Japanese patients with persistent, recurrent, or metastatic cervical cancer.

Methods: In this multicenter observational study at four Japanese institutions, 100 patients with recurrent, persistent, or advanced cervical cancer received pembrolizumab or cemiplimab. Primary endpoints were objective response rate (ORR) and the incidence of immune-mediated adverse events (imAEs) and grade 3-5 AEs. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Logistic and Cox regression were used to explore prognostic factors.

Results: Eighteen patients (18%) achieved complete response and 44 (44%) partial response, yielding an ORR of 62.0% and a disease control rate of 77.0%. Median PFS and OS were 10.4 and 22.0 months, respectively. ORR was 74.0% in the first-line setting and 29.6% in the second-line setting. Among patients who met KEYNOTE-826 eligibility criteria, ORR was 82.9% and median PFS 16.1 months. Cemiplimab, which was mainly used as off-label retreatment in frail or previously ICI-exposed patients, showed limited activity (ORR 5.6%). ImAEs occurred in 45.0% of patients, with grade 3-5 events in 19.0% and six treatment-related deaths. Poor performance status and recurrent disease were associated with lower response and shorter PFS, whereas PD-L1 tumor proportion score ≥ 50% and grade 3-5 imAEs were associated with longer PFS.

Conclusion: In this real-world cohort, ICIs, particularly pembrolizumab, demonstrated substantial antitumor activity with acceptable toxicity in Japanese patients with advanced cervical cancer, especially when used as first-line therapy and in patients fulfilling KEYNOTE-826 eligibility criteria.

Background: The evolving prognosis of colorectal cancer (CRC) over extended periods following surgery has not been comprehensively characterized. This study aimed to delineate long-term patterns in conditional survival (CS), evaluate the changing relevance of CRC recurrence surveillance versus management of fatal non-cancer conditions, and suggest follow-up indicators tailored to postoperative duration.

Methods: We examined trends in conditional overall survival (cOS), disease-specific survival (cDSS), and non-disease-specific survival (cNDSS) by tumor stage in 2,996 patients (stage 0-IV) who underwent surgical resection for CRC. Furthermore, we conducted a multivariate analysis in a cohort of 1,529 patients surviving more than 5 years to identify predictors of long-term survival.

Results: Over a median observation period of 60.4 months, 745 deaths were recorded (478 CRC-related, 243 unrelated to CRC, and 24 unknown). Stage-wise CS analyses revealed crossover points of cDSS and cNDSS at 3 years post-surgery in stage II and at 6 years in stages III/IV. Multivariate analysis identified age ≥ 80, CEA ≥ 5.0 ng/mL, CA19-9 ≥ 37.0 U/mL, albumin ≤ 4.1 g/dL, anemia, RDW ≥ 14.9%, and platelet count ≤ 150 × 10⁹/L as independent risk factors in 5-year survivors.

Conclusions: The importance of CRC recurrence surveillance was most prominent within the first 3 years after surgery in stage II and within 6 years in stages III/IV. Our findings underscore the need to customize surveillance strategies based on duration since surgery and indicate that the aforementioned clinical parameters may serve as useful markers in 5-year survivors.

Background: Comprehensive genomic profiling (CGP) has been publicly reimbursed in Japan for 5 years, yet its impact on survival in real-world provincial settings remains unclear.

Methods: We retrospectively analyzed 914 patients with solid tumors who underwent tissue- or blood-based CGP at our institute between December 2019 and July 2023.

Results: The median age of patients was 66 years. Colorectal (18.9%) and pancreatic (16%) cancers were most common. Actionable alterations were detected in 87.5%, and druggable alterations in 58.3% of patients. Genomically matched therapy was administered to 10.9% of patients, who had better survival than those with druggable alterations who did not receive therapy [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.42-0.74] or those without actionable alterations (HR 0.63, 95% CI 0.47-0.83). A progression-free survival ratio > 1.3 was observed in 39.4% of patients. Multivariate analysis confirmed matched therapy was an independent favorable prognostic factor. Despite lower detection and treatment rates with blood-based CGP because of false negatives, survival benefit was preserved. Patients referred from external institutions had delayed CGP testing, but treatment benefit was slightly greater. Survival improvement was not observed in patients undergoing four or more prior regimens.

Conclusion: CGP-guided matched therapy may improve survival even in provincial settings. To optimize clinical utility, the appropriate CGP panel must be offered to the appropriate patient at the optimal time.

Background: The clinical utility of immediate complete lymph node dissection (CLND) following positive sentinel node (SN) remains controversial in acral melanoma (AM), in Asian populations where AM is more prevalent. This study aimed to compare the survival outcomes of immediate CLND versus observation (OBS) in Japanese patients with stage III sole AM and positive SN.

Methods: This retrospective, multicenter study included 154 patients (CLND: 90, OBS: 64) with stage III sole AM with positive SN, across 44 Japanese institutions. Recurrence-free survival (RFS), distant metastasis-free survival (DMFS), regional metastasis-free survival (RMFS), and overall survival (OS) were compared between the two groups. Cox multivariable analysis and propensity score matching (PSM) were performed to adjust for potential confounders.

Results: With a median follow-up of 3.9 years, non-significant differences were observed in RFS, DMFS, RMFS, or OS between the CLND and OBS groups (P = 0.33, 0.32, 0.08, and 0.21, respectively). Cox multivariable analysis identified N3a nodal stage as an independent negative factor for OS (HR: 2.6, P = 0.02), whereas CLND and other variables were not associated. After PSM, 92 (46 each) were matched. RFS and DMFS remained comparable (P = 0.16 and 0.19), with a non-significant trend toward improved RMFS in the CLND group (P = 0.08), and no difference in OS (P = 0.14).

Conclusions: Immediate CLND did not provide a survival advantage over OBS in patients with stage III sole AM and positive SN. These findings do not support the routine use of CLND in this population. Trial registration Not applicable.