tbuckley/cabot-search huggingface dataset:
Reporting of immune-related adverse events (irAEs) in US Food and Drug Administration (FDA) approvals of immune checkpoint inhibitors.
Authors: Shaili Tapiavala, Mina A. Shenouda, Vaibhav G. Patel, Andrew A. Davis
Journal: Journal of Clinical Oncology (2024)

e14693 Background: Evaluating immune checkpoint inhibitor (ICI) toxicity is complex given the interplay between the host immune system and tumor microenvironment leading to unpredictable timing and severity of irAEs. Monitoring of irAEs is critical as they can cause significant impact on morbidity and quality of life. Thus, we evaluated the consistency and pattern of reporting of irAEs in trials leading to FDA drug approvals. Methods: Using the FDA website, we identified 73 primary articles for ICI FDA approvals over a 10-year period (2011-2021). Data were collected independently by all authors as categorical variables for reporting of any grade and grade 3 or higher toxicity in the trial arm that led to FDA approval for 29 irAEs classified by the National Comprehensive Cancer Network Version 1.2024 guidelines. Our analyses were based on a binary classification of reported versus not reported, including the manuscript text, tables, and supplement, and reporting trends were analyzed based on the study year, phase, primary tumor, and monotherapy versus combination ICI therapy. Results: The majority of approvals were associated with Phase II (N=22) or Phase III (N=39) studies. Approvals included 14 primary tumors and 2 tumor agnostic approvals with the most common tumors including lung (N=22) and skin (N=14). irAE reporting ranged between 0% and 100% with a mean of 40% and a standard deviation of 35. Across the 29 irAEs, 45% were categorized as severely underreported with less than 25% reporting in trials, 17% were classified as underreported in 26-50% of trials, 17% were moderately reported in 51-75% of trials, and 21% were well reported in at least 75% of trials. For example, fatigue, diarrhea, and hypothyroidism were well reported at 100%, 99%, and 93%, respectively, while myocarditis, aseptic meningitis, and giant cell arteritis were severely underreported at 18%, 4%, and 1%, respectively. Additionally, certain systems were more reported than others, including gastrointestinal (100%) and endocrine (97%), while other systems were inconsistently reported such as cardiology (15%) and neurology (48%) (see Table). Conclusions: Our study identified significant inconsistencies in irAE reporting in clinical trials that led to ICI FDA approvals. In particular, rarer irAEs were reported infrequently while more common irAEs were well reported. Unified efforts are needed to standardize the irAE reporting in the primary literature to ensure reliable dissemination of information for timely recognition and treatment in clinical practice. [Table: see text]
Novel TROP2-targeted CAR T cells with high specificity and sustained efficacy for solid tumors in animal models.
Authors: Chih-Chun Liu, Tzer-Min Kuo, Jiann-Shiun Lai, Ming-Tain Lai
Journal: Journal of Clinical Oncology (2024)

e14563 Background: CAR T cell therapy, successful in hematological malignancies, encounters challenges against solid tumors due to immune exhaustion and senescence within the tumor microenvironment. The imperative need for an optimal tumor target antigen is evident in advancing CAR T therapy. TROP2, a membrane-associated glycoprotein, is highly expressed in diverse cancers, including cervical, bladder, esophageal, ovarian, and endometrial cancers. TROP2 overexpression, approaching 100% in cervical and hormone-resistant prostate cancer, correlates inversely with prognosis and survival, presenting TROP2 as a promising CAR T therapy target. This study engineered the novel TROP2 antibody R4702, featuring a distinct binding epitope from Sacituzumab and Datopotamab, to develop TROP2-specific CAR T cells and evaluated their efficacy against a spectrum of solid tumors. Methods: Expansion of CAR T Cells and Cytotoxicity: CAR T cells were created through lentivirus-mediated genetic engineering with the TROP2 antibody, followed by 10 days of expansion. T cell differentiation was evaluated, and luciferase-encoding target cells incubated with varying CAR T cell ratios overnight were quantified luciferase activity. In Vivo Efficacy and Persistence: CAR T cells were adoptively transferred into ASID mice with tumors. In vivo tumor imaging used luciferase activity, and calipers monitored tumor size weekly. CAR T cell persistence assessed their ability to suppress rechallenged tumor growth. Results: R4702, a novel TROP2-specific antibody, displayed high binding affinity to a distinct epitope. Post- ex vivo expansion, R4702 CAR T cells showed a substantial increase (100 to 200-fold) over 10 days, with a high expression level (50~80%) of R4702 CAR on T cells. Over 60% of R4702 CAR T cells displayed a less differentiated status, characterized by a CD62L+ population comprising T SCM and T CM . In vitro cytotoxicity revealed potent and specific efficacy against various TROP2-positive cancer cell lines, with no observed killing activity against TROP2-negative cells. In vivo efficacy of R4702 CAR T cells demonstrated 100% tumor growth inhibition within 30 days post-treatment across diverse xenograft models. Importantly, R4702 CAR T cells exhibited enduring anti-tumor efficacy against successive tumor challenges in xenograft models of pancreatic, gastric, NSCLC, TNBC, and ovarian cancers. In a head-to-head comparison with Sacituzumab and Datopotamab CAR T, R4702 demonstrated superior anti-tumor efficacy to Sacituzumab and comparable efficacy with Datopotamab in the BxPC-3 CDX model of pancreatic cancer. Conclusions: A novel TROP2-specific R4702 CAR T cell, developed, showcased robust tumor-killing capabilities. The anti-tumor activity persisted upon repeated tumor challenges across various xenograft models, underscoring the potential of R4702 CAR T cells as a promising therapeutic strategy.
Genetic drivers of severe skin toxicity with immune checkpoint inhibitors (ICIs) in Asian patients.
Authors: Kohei Yoshimine, Hiroki Goto, Kana Yamada, Tamaki Fukuyama, Tetsuro Oda, Runa Iwakami, Koji Takahashi, Monika Dulloo Kaul, G Scott Chandler, Rajat Mohindra, Katrin Madjar
Journal: Journal of Clinical Oncology (2024)

2667 Background: ICIs may cause severe skin toxicity associated with significant patient (pt) impact. Published data suggests Asian pts might be at higher risk of skin immune-related adverse events (SirAEs). Variation in human leukocyte antigen (HLA) is known to predispose to autoimmune (AI) conditions, but there is limited data to understand genetic drivers of severe SirAEs. Methods: The incidence of severe SirAEs was correlated with 30 HLA alleles of interest in 2 cohorts totaling 18 Asian pts (Dermatitis bullous n=4, Erythema multiforme n=10, Stevens-Johnson syndrome n=3, Toxic skin eruption n=1) treated with atezolizumab (A) across tumor types as monotherapy or as part of combinations- 8 Japanese pts received A in a non-interventional study (trial ID: UMIN000048702) and 10 Asian pts were enrolled in Roche trials with A. Data from the 18 cases was compared to 3 different controls of Asian pts identified from Roche trials with A (i.e. pts without any irAEs n=148, pts without SirAEs n=225, pts without severe SirAEs n=390). For each HLA allele, positive predictive value (PPV), negative predictive value (NPV), sensitivity, specificity, (unadjusted) odds ratio (OR) and corresponding 95%-confidence interval (CI) were evaluated. Case-control populations were obtained by risk-set sampling with exact matching on indication, treatment arm and sex, and used in age-adjusted conditional logistic regression models to assess associations between each HLA allele and severe SirAEs. Results: There was an association between some HLA alleles and severe SirAEs, but sensitivity was low (&lt;30%) and 1-NPV was only slightly smaller than background prevalence. Results for five HLA alleles with OR&gt;1.5 in either the unadjusted or adjusted analysis compared to controls without severe SirAEs are presented in table. Results were consistent across the three control populations. Conclusions: Five HLA alleles previously reported in AI disorders were associated with severe SirAEs in Asian pts receiving A. Although the effect size is insufficient to be considered clinically relevant, further research is warranted to better characterize the pt-level drivers of severe SirAEs in Asians pts. Clinical trial information: UMIN000048702 . [Table: see text]
Erythrocyte-αPD-1 conjugates overcome resistance to checkpoint blockade immunotherapy: A first-in-human study.
Authors: Xiaoqian Nie, Liu Yang, Yuehua Liu, Zheling Chen, Xiaofei Gao
Journal: Journal of Clinical Oncology (2024)

2557 Background: While the immune checkpoint blockade (ICB) therapy has revolutionized the field of tumor therapy. the resistance remains a major challenge. We have previously developed WTX-212, an erythrocyte-antibody conjugate covalently linking anti-PD-1 antibody to erythrocyte membranes. Unlike conventional antibodies, WTX-212 exhibits natural accumulation in the spleen and remodels the splenic immune landscape in tumor-bearing mice. WTX-212 treatment efficiently activates CD8+ T cells in the spleen, which subsequently infiltrate into tumors and exhibit anti-tumor cytotoxicity. Additionally, activated T cells reduce the splenic reservoir of Myeloid-derived suppressor cells (MDSC) and those within tumors, further enhancing overall anti-tumor responses. Pre-clinical studies have demonstrated that WTX-212 can significantly suppress tumor growth in xenograft tumor models resistant to anti-PD-1 immunotherapies. A first-in-human (FIH) clinical trial is now investigating its potential in human cancer patients. Methods: The FIH trial (NCT05707325) is aimed to investigate the safety, pharmacokinetics and preliminary efficacy of WTX-212 in cancer patients with advanced malignancies. All of patients had previously received anti-PDs therapies and developed resistance to these treatments. By Feb 5 th , 2024, the tumor lesions were assessed using RECIST v1.1 criteria. Blood and tumor samples were collected for correlative analysis. Results: 7 metastasized patients with various solid tumors, having undergone a median of 3.1 prior lines of therapy (ranging from 1-6), received WTX-212 monotherapy. None of patients treated with WTX-212 experienced treatment-related adverse events greater than Grade 3, indicating a high safety profile. WTX-212 was detectable in peripheral blood at the end of cycle in a dose dependent manner. Disease control was achieved in 5/7 patients (DCR=71%). Specifically, a patient with esophageal cancer, achieved a confirmed complete remission after 6-cycle treatment. Additionally, two patients, one with esophageal cancer (3L) and another with HPV-negative cervical cancer (4L), maintained stable disease for over 40 and 30 weeks, respectively. Consistent with our pre-clinical findings, a substantial reduction in MDSCs were observed in 6/7 patients (ranging from 24%-82%). Furthermore, a median 1.5-fold increase in T cells was noted in all patients in the peripheral blood after the 1 st cycle of the treatment. Conclusions: WTX-212 treatment is safe and tolerable and shows promising clinical signs in cancer patients resistant to anti-PD-1 immunotherapy, supporting further investigation and exploration of WTX-212 monotherapy and combination therapy. Clinical trial information: NCT05707325 .
A rapid strategy to develop personalized cancer nanovaccines for different immunogenic tumors.
Authors: Xia Li, Naoto Shirahata, Tomohiko Yamazaki, Nobutaka Hanagata
Journal: Journal of Clinical Oncology (2024)

e14670 Background: Therapeutic cancer vaccines aim to train the immune system and elicit antitumor immune responses, which are expected to fill the unmet medical need of immune checkpoint inhibitors. Despite tremendous efforts over the past decades, it remains challenging to prepare personalized cancer vaccines using a facile and rapid approach due to tumor diversity. CpG-ODN is a promising immunoadjuvant in cancer immunotherapy, and many clinical trials have been performed or are ongoing. However, commonly used phosphorothioate-modified CpG ODN easily induces protein aggregation and its long-term side effects are concerned. Here, we designed hollow large-pore mesoporous organosilica with sulfide bond to simultaneously load unmodified CpG-ODN with guanine-quadruplex (G4) structures and different tumor antigens to prepare personalized cancer vaccines in a simple, fast, and effective way. Methods: High-immunogenicE.G7-OVA lymphoma or low-immunogenic Lewis lung carcinoma (LLC) cells were subcutaneously inoculated into the left flanks to establish tumor-bearing mice. On days 4, 7, and 10 post tumor inoculation, cancer vaccines prepared using model antigen (OVA) or autologous tumor antigen (LLC tumor cell lysate) were subcutaneously injected into the right flanks of mice, respectively. Saline group, free tumor antigen group, free tumor antigen + CpG-ODN group, tumor antigen + organosilica group were used as controls. The size of tumors was monitored. Results: Cancer vaccines against E.G7-OVA showed high loading efficiencies of &gt;95% for both CpG-ODN and OVA, triggered antitumor immune response with high percentages of CD4 + , CD8 + , tetramer + CD8 + T cells in splenocytes, and effectively inhibited the growth of established tumor, compared with free OVA, free OVA + CpG-ODN, free OVA + organosilica groups. Cancer vaccines against LLC exhibited high loading efficiencies of &gt;95% and &gt;80% for CpG-ODN and LLC tumor cell lysate, activated antitumor immune response with high percentages of CD4 + and CD8 + T cells in splenocytes and CD8 + T, NK and M1 cells in tumor sites, and effectively inhibited the growth of established tumor, compared with control groups. Conclusions: Codelivery of CpG-ODN and different tumor antigens using hollow large-pore mesoporous organosilica elicits antitumor immunity against both high-immunogenic and low-immunogenic tumors.
Cytotoxic function of human natural killer cells is transiently inhibited by transforming growth factor beta (TGFβ).
Authors: Anjali Patel, Giuseppe Maiocco, Catherine Mirto, Donald S. Torry, Andrew Wilber
Journal: Journal of Clinical Oncology (2024)

e14557 Background: Natural killer (NK) cells can eliminate early neoplastic cells, however, their efficacy as an adoptive therapy for solid tumors is limited. We have shown that NK cells recovered from human kidney tumors are CD56 pos /CD16 dim/neg , poorly cytotoxic, and produce vascular endothelial growth factor (VEGF). These features are analogous to human decidual NK (dNK) cells that support the development and growth of the placenta during implantation. Transforming growth factor beta (TGFβ) is found at high levels in the decidua and kidney tumor environment, and is known to convert peripheral blood NK (pNK) cells to dNK-like cells in vitro. We hypothesized that TGFβ-mediated inhibition of NK cell proliferation and function is transient and therefore reversible. Methods: pNK cells were isolated from healthy donors (HD) by negative selection or purchased from ATCC (NK-92; CRL-2407). RT-qPCR and flow cytometry were used to assess NK markers: CD56, CD16 NKp46, CD49a, CD69; TGFβ receptors R1, R2, R3; VEGF; and cytokines IFNγ, TNFα. NK cells were cultured for 4-5 days with proliferative cytokines IL2 or IL15 alone and in combination, and without or with TGFβ (2-5 ng/mL). Cytotoxic function of NK cells (effectors) was quantified by lysis of human K562 cells engineered to express firefly luciferase (targets). Statistics (ANOVA/t-test) were performed using GraphPad Prism with p≤0.05 considered significant. Results: pNK cells from HD were CD56 pos /CD16 pos and NK-92 cells were CD56 pos /CD16 neg as reported. Both expressed all three TGFβ receptors, required IL2 or IL15 to survive in culture and were potently cytotoxic against K562 targets. TGFβ treatment of NK cells cultured with IL2 or IL2 plus IL15 suppressed proliferation by 20% and potently inhibited cytotoxic ability (85% reduction; p≤0.05). TGFβ caused significant changes in CD49a (35% increase), CD69 (45% increase) and IFNγ (50% decrease) but had no effect on NKp46, VEGF, or TNFα. TGFβ-mediated changes in NK cell phenotype and function reverted to normal when NK cells were returned to standard culture conditions for 4-5 days. Conclusions: Despite differences in CD16 expression, pNK cells and NK-92 cells are potently cytotoxic and represent an effective anti-cancer therapy. TGFβ limits this potential by blocking the proliferative effects of IL2 and IL15 and quelling cytotoxic function. TGFβ caused increased expression of integrin CD49a, a marker of tissue resident immune cells, and the early lymphocyte activation marker CD69. Augmentation of these surface markers was concomitant with diminution of IFN-γ, a cytokine critical for cell-mediated responses to tumors. These collective changes are akin to dNK cells that are not cytotoxic and instead support the implant. Importantly, all alterations were restored if NK cells were no longer exposed to TGFβ. Thus, inhibition of TGFβ signaling could preserve NK function in the tumor environment.
Dose escalation of KY-0118, PD-1, and IL-2v due-target fusion protein in patients with advanced renal clear cell carcinoma, urothelial carcinoma, and malignant melanoma.
Authors: Guoxiang Wu, Dianwen Ju, Yahui Su, Helen Yu
Journal: Journal of Clinical Oncology (2024)

e14505 Background: KY-0118 is an anti-PD1 and IL-2v(variant) fusion protein for advanced solid tumors. The non-α biased design reduces the binding to IL2-Raβγ and enhanced binding to PD-1 &amp; IL2-Rβγ positive TILs to drive increased proliferation and activation of NK and CD8 + T cells without unwanted expansion of Tregs. KY-0118 adopts specific single design, only 67kDa MW thus obtains excellent tumor penetration activity. The preclinical data shows higher antitumor activity in several CDX models compared with nivolumab and IL2wt. KY-0118 monotherapy is currently in Phase I escalation. Methods: The phase I dose escalation is a traditional 3+3 design, KY-0118 on Days 1, 8 and 15, 21-day treatment cycle, 9 dose levels (0.3μg/kg-64μg/kg) or higher doses of 3 to 6 patients are planned. The dose expansion cohort is currently enrolling. The primary endpoint was to evaluate the safety, tolerability, and determine the DLT, MTD, RP2D of KY 0118 when given alone. Secondary objectives are PK/PD characteristics and preliminary evidence of efficacy via ORR per RECIST v1.1 and iRECIST. Results: Up to Jan 31, 2024, 21 patients have been treated, the median number of prior lines of systemic therapy was 2. The dose level 8 (48µg/kg) of DLT observation period is ongoing, no DLT was observed in the administered dose groups. Most of TEAEs are transient grade 1-2, no TEAE led to withdrawal from this study. The most common nonhematologic TRAEs were pyrexia, flu-like symptoms, nausea, fatigue. 2 patients had grade 3 hematologic toxicity. Treatment-related sAEs were observed in one patient (include nausea, vomiting, and pulmonary embolism, now recovered and continuing treatment). No patients experienced complete or partial response, but several showed evidence of antitumor activity, at the dose of 36 ug/kg, 21% shrinkage of target lesions in a patient with RCC, the DCR for the 12, 24, and 36μg/kg dose levels are 33%, 75%, and 67%, respectively. Conclusions: These preliminary data suggest that KY-0118 demonstrated a manageable safety profile and encouraging early evidence of activity has been observed in locally advanced and/or metastatic solid tumors. Enrollment is ongoing, further results are forthcoming. Pts: 21; AEs: 399; TEAEs: 289 (100%); AESI: 13; sAEs: 8. Clinical trial information: NCT06175780 .
Retrospective analysis on association of body mass index and immune checkpoint inhibitor response.
Authors: Akshee Batra, Abhinav Vyas, Atulya Aman Khosla, Akshit Chitkara, David Alejos, Xiaocao Xu, Karan Jatwani, Hibba Tul Rehman, Shahid Sattar Ahmed, Rohit Singh
Journal: Journal of Clinical Oncology (2024)

e14536 Background: The relationship between Body Mass Index (BMI) and cancer is a complex. We aim to study the impact of BMI on the response to immunotherapy in cancer patients. Methods: We did a retrospective observational study to investigate the influence of different BMI groups on patients receiving Immune Checkpoint Inhibitors (ICIs) at the University of Vermont Cancer Centre. We examined the medical records of people who received ICIs between January 2017 and June 2022 and collected demographic data, including age, sex, ethnicity, cancer stage, BMI, type and metastasis. We looked at Hazard Ratio (HR) in BMI subcategories compared to normal. The occurrence of immune-related adverse events (irAEs), metastasis and receipt of chemotherapy in different BMI subgroups was evaluated with relative risks (RRs). Results: A total of 288 cases were identified, out of which 269 had documented BMI, including 58% males, 94.8% whites with 64.17 years mean age. Lung cancer was most common at 41.3%, 46.5% were and 63.2% were stage 4. Total 71.4% of people received Pembrolizumab and 42.8% had concomitant chemotherapy. The median ECOG was 1 and the Charlson comorbidity index was 6. irAEs observed in 33% of cases, whereas mortality in 36%. The BMI distribution had 36.1% normal, 27.1% overweight, 16.5% obese, 14.5% extremely obese and 5.6% underweight. The HR in underweight subgroup was significant at 5.223 (p &lt;0.001; 95CI: 2.2 to 12.4) compared to normal. The HR of overweight, obese and extremely obese decreased with HR of 1.15, 0.77 and 0.18 respectively but wasn’t significant as seen in Table 1. Table also shows that relative risk of irAEs, cancer stage, metastasis and concomitant chemotherapy were not significant. Conclusions: Clinically significant association was found between being underweight and mortality in cancer patients receiving immunotherapy. [Table: see text]