Anti-cytotoxic T-lymphocyte Antigen Research Articles

Phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: the desmoid tumors

BackgroundDual inhibition using anti-programmed death-1 (PD-1) and anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) checkpoint inhibitors has proven effective in many cancers. However, its efficacy in rare solid cancers remains unclear. Desmoid tumors...

Enhancing Dendritic Cell Cancer Vaccination: The Synergy of Immune Checkpoint Inhibitors in Combined Therapies.

Dendritic cell (DC) cancer vaccines are a promising therapeutic approach, leveraging the immune system to fight tumors. These vaccines utilize DCs' ability to present tumor-associated antigens to T cells, triggering a robust immune response. DC vaccine development has progressed through three generations. The first generation involved priming DCs with tumor-associated antigens or messenger RNA outside the body, showing limited clinical success. The second generation improved efficacy by using cytokine mixtures and specialized DC subsets to enhance immunogenicity. The third generation used blood-derived DCs to elicit a stronger immune response. Clinical trials indicate that cancer vaccines have lower toxicity than traditional cytotoxic treatments. However, achieving significant clinical responses with DC immunotherapy remains challenging. Combining DC vaccines with immune checkpoint inhibitors (ICIs), such as anticytotoxic T-lymphocyte Antigen 4 and antiprogrammed death-1 antibodies, has shown promise by enhancing T-cell responses and improving clinical outcomes. These combinations can transform non-inflamed tumors into inflamed ones, boosting ICIs' efficacy. Current research is exploring new checkpoint targets like LAG-3, TIM-3, and TIGIT, considering their potential with DC vaccines. Additionally, engineering T cells with chimeric antigen receptors or T-cell receptors could further augment the antitumor response. This comprehensive strategy aims to enhance cancer immunotherapy, focusing on increased efficacy and improved patient survival rates.

Abstract PO3-06-09: A phase II study of nivolumab plus ipilimumab and androgen receptor antagonist bicalutamide to stimulate thymic T cell generation in HER2-negative metastatic breast cancer

Abstract Background: Systemic chemotherapy is used commonly in breast cancer and is associated with lymphopenia, potentially limiting efficacy of immune checkpoint blockade. The androgen receptor (AR) serves as a negative regulator of thymic function. AR antagonists, such as bicalutamide, may stimulate thymic production of naïve T-cells, which may help to restore lymphocyte diversity and augment immunotherapy response. The AR is expressed in 50% of hormone receptor negative (HR-) metastatic breast cancer (MBC) and >75% of HR+ MBC, and bicalutamide is clinically active with stable disease as best response. We hypothesize that bicalutamide could be combined with dual immune checkpoint blockade (anti-programmed death 1, nivolumab; plus anti-cytotoxic T-lymphocyte antigen 4, ipilimumab), stimulating T-cell production and resulting in durable clinical response. Methods: This is a phase II Simon 2-stage trial of nivolumab (240 mg IV q2w), ipilimumab (1 mg/kg IV q6w), and bicalutamide (150mg oral daily) for first- or second-line treatment of HER2-negative MBC (NCT03650894). The primary endpoint is iRECIST 24-week clinical benefit rate (CBR), evaluated separately for HR+ MBC (n=15) and AR+/HR- MBC (n=15). An optimum Simon 2-stage design (80% power, 5% one-sided alpha) is employed to evaluate an alternative hypothesis of >50% CBR compared to historical control of < 30% CBR for conventional chemotherapy, with expansion of each cohort planned if ≥6/15 responses are observed. Secondary outcomes include best overall objective response rate (ORR), progression-free and overall survival (PFS,OS), and safety. Exploratory endpoints include assessment of peripheral T-cell counts and T cell receptor excision circles (TREC PCR, Mayo Laboratories, a surrogate of thymic T-cell production) over time. Results: Durable responses were observed, with an ongoing complete response at 41+ months in a patient who discontinued due to toxicity (AR+/HR- cohort, PD-L1 CPS score 3%). Therapy was tolerated with a toxicity profile consistent with prior studies of ipilimumab & nivolumab, with five subjects (19%) requiring treatment discontinuation related to toxicity. Outcomes by cohort and PDL1 are summarized in Table 1. Using mixed effects linear models, therapy was associated with a significant expansion of CD8+ T cells (23/mcL/month, p< .01) but not CD3+ T cells (7/mcL/month, p=.59) or CD4+ T cells (4/mcL/month, p=.65). Baseline TREC counts were higher in younger participants (mean: < 50y 2156/mcL; 50-65y 961/mcL; >65y 311/mcL). TRECs did not increase globally, however TREC expansions were observed in several younger participants. Conclusions: The regimen of ipilimumab, nivolumab, plus bicalutamide is safe and clinically active in 1st/2nd-line HER2-negative MBC. Neither cohort crossed the Simon futility barrier for cohort expansion, however durable responses were observed including in PD-L1-negative patients, highlighting the unmet need for biomarkers to identify candidates for chemotherapy-sparing checkpoint blockade. Further research is indicated to evaluate the impact of AR antagonists on T-cell function and thymic stimulation in MBC. Acknowledgements: Drug and study support was provided by Bristol-Myers Squibb and The BMS International Immuno-Oncology Network (II-ON). Clinical outcomes XX XX HR: hormone receptor; AR: androgen receptor; CPS: PD-L1 combined positive score Citation Format: David Page, Alexander Hall, Krystle Collins, Nicole Moxon, Staci Mellinger, Tracy Kelly, Aysha Kelley, Nicole Fredrich, Amanda Seino, Gabriella Liberatore, Alison Conlin, Zheng Topp, Kelly Perlewitz, Sasha Stanton, Walter Urba, Yaping Wu, Maritza Martel, Zhaoyu Sun, Yoshinobu Kogushi, William Redmond, Tiffany Traina, Ayca Guculp. A phase II study of nivolumab plus ipilimumab and androgen receptor antagonist bicalutamide to stimulate thymic T cell generation in HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-06-09.

Abstract 6425: Harnessing big data from pan-cancer concerning more than 1300 patients with immune checkpoint inhibitors identifies novel predictive biomarkers

Abstract Immune-checkpoint inhibitors (ICIs) have revolutionized cancer therapy, yet many patients face the challenges of either not benefiting or developing resistance to ICIs. Advances in genome sequencing allow the exploitation of high-dimension oncological data in the research and development of precision immuno-oncology. We conducted a comprehensive literature review involving cancer patients treated with ICIs [anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), or their combination] and collected available transcriptomic data from pretreatment biopsies along with corresponding clinical outcomes. Biomarkers for ICI response were independently investigated within each study using the logistic regression method and combined with the odds ratio (OR) for meta-analysis. A total of 210 formalin-fixed paraffin-embedded pan-cancer samples with pretreatment biopsies from the National Cancer Center retrospective cohort were collected for validation. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC) were employed to validate the stable and clinically applicable utility of the genomic biomarker identified in our analysis. Across 18 studies, we identified 1106 cancer patients who received immunotherapy with pre-treatment transcriptomic data, including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), stomach adenocarcinoma (STAD), glioblastoma (GBM), and bladder urothelial carcinoma (BLCA), of which 8421 genes were available in all datasets. Meta-analysis based on a common effect model revealed that 332 genes were positively correlated with a favorable response to ICIs, and 404 genes were negatively associated with the therapeutic outcome, with all pooled OR being statistically significant (P <0.05). We identified a novel biomarker, ZBED2 (Zinc Finger BED-Type Containing 2), which demonstrated superior predictive value over other biomarkers for ICI efficacy (pooled OR, 0.596; 95% CI, 0.450-0.788, P =0.002). Similarly, RT-qPCR (AUC: 0.821) and IHC (AUC: 0.789) results further validated the predictive utility for ICI response in the real-world cohort of 210 cancer patients with pretreatment samples receiving ICIs. Additionally, we observed that the expression of ZBED2 was favorably associated with the overall survival of patients receiving immunotherapy (HR: 0.72). In summary, our study provides a in-depth analysis of potentially predictable biomarkers for ICIs in cancer and highlights the potential of large-scale meta-analyses in identifying stable biomarkers. ZBED2 emerges as a novel predictive biomarker for ICIs and may guide the implementation of risk-related therapeutic strategies. Citation Format: Peng Wu, Chaoqi Zhang, Ao Shen, Xuanyu Gu, Nan Sun, Jie He. Harnessing big data from pan-cancer concerning more than 1300 patients with immune checkpoint inhibitors identifies novel predictive biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6425.

Treatment of Stage III Resectable Melanoma-Adjuvant and Neoadjuvant Approaches.

Patients with stage III resectable melanoma carry a high risk of melanoma recurrence that ranges from approximately 40% to 90% at 5 years following surgical management alone. Postoperative systemic adjuvant therapy targets residual micrometastatic disease that could be the source of future recurrence and death from melanoma. Randomized phase III adjuvant trials reported significant improvements in overall survival with high-dose interferon α in 2 of 3 studies (compared with observation and GMK ganglioside vaccine) and with anti-cytotoxic T-lymphocyte antigen 4 ipilimumab at 10 mg/kg compared with placebo and ipilimumab 3 mg/kg compared with high-dose interferon α. In the modern era, more recent phase III trials demonstrated significant recurrence-free survival improvements with anti-programmed cell death protein 1, pembrolizumab, and BRAF-MEK inhibitor combination dabrafenib-trametinib (for BRAF mutant melanoma) versus placebo. Furthermore, anti-programmed cell death protein 1, nivolumab and pembrolizumab have both been shown to significantly improve recurrence-free survival as compared with ipilimumab 10 mg/kg. For melanoma patients with clinically or radiologically detectable locoregionally advanced disease, emerging data support an important role for preoperative systemic neoadjuvant therapy. Importantly, a recent cooperative group trial (S1801) reported superior event-free survival rates with neoadjuvant versus adjuvant therapy. Collectively, current data from neoadjuvant immunotherapy and targeted therapy trials support a future change in clinical practice in favor of neoadjuvant therapy for eligible melanoma patients.

New strategies in the diagnosis and treatment of immune-checkpoint inhibitor-mediated colitis.

Immune-checkpoint inhibitor-mediated colitis (IMC) is an increasingly recognized adverse event in cancer immunotherapy, particularly associated with immune checkpoint inhibitors (ICIs) such as anti-cytotoxic T-lymphocyte antigen-4 and anti-programmed cell death protein-1 antibodies. As this revolutionary immunotherapy gains prominence in cancer treatment, understanding, diagnosing, and effectively managing IMC becomes paramount. IMC represents a unique challenge due to its immune-mediated nature and potential for severe complications. However, a precise picture of IMC pathophysiology is currently unavailable. Therefore, we aimed to summarize the existing data while acknowledging the need for further research. This comprehensive review explores the mechanisms underlying ICIs, gastrointestinal adverse effects, and, in particular, IMC's incidence, prevalence, and features. Our review also emphasizes the importance of recognizing IMC's distinct clinical and histopathological features to differentiate it from other forms of colitis. Furthermore, this paper highlights the urgent need for evolving diagnostic methods, therapeutic strategies, and a multidisciplinary approach to effectively manage IMC.

Discovery and identification of the prognostic significance and potential mechanism of FMO2 in breast cancer.

Flavin containing dimethylaniline monoxygenase 2 (FMO2), is downexpressed in diverse tumors and displays vital roles in tumorigenesis. However, the prognostic value and potential mechanism of FMO2 in breast cancer remain unclear. The expression of FMO2 was analyzed and the relationship between FMO2 expression level and clinical indicators in breast cancer was analyzed. Then the prognostic value of FMO2 in breast cancer was assessed. The FMO2-correlated genes were obtained, and the highest-ranked gene was chosen. The expression, therapeutic responder analysis, and gene set enrichment analysis of the highest-ranked gene were conducted. FMO2 was downregulated in breast cancer and was closely related to clinical indicators. Patients with decreased FMO2 expression showed poor overall survival, post-progression survival, relapse-free survival, and distant metastasis-free survival. FMO2 correlates with N/ER/PR subgroups in breast cancer and patients with high FMO2 levels were sensitive to anti-programmed cell death protein 1, anti-programmed death-ligand 1, and anti-cytotoxic T-lymphocyte antigen 4 immunotherapies. Mechanically, FMO2 was positively and highly correlated with secreted Frizzled-related protein 1 (SFRP1), which was downregulated in breast cancer due to hypermethylation. Moreover, SFRP1 was correlated to pathological complete response and relapse-free survival status at 5 years regardless of any chemotherapy, hormone therapy, and anti-HER2 therapy. Gene set enrichment analysis revealed enrichment of component and coagulation cascades, focal adhesion, protein export, and spliceosome. FMO2 was lower expressed in breast cancer than normal tissues and contributes to subtype classification and prognosis prediction with co-expressed SFRP1.

Update in Immunotherapy for Advanced Non-Small Cell Lung Cancer: Optimizing Treatment Sequencing and Identifying the Best Choices.

The introduction of immunotherapy has brought about a paradigm shift in the management of advanced non-small cell lung cancer (NSCLC). It has not only significantly improved the prognosis of patients but has also become a cornerstone of treatment, particularly in those without oncogenic driver mutations. Immune checkpoint inhibitors (ICIs) play a crucial role in the treatment of lung cancer and can be classified into two main groups: Anti-cytotoxic T lymphocyte antigen-4 (Anti-CTLA-4) and anti-T-cell receptor programmed cell death-1 or its ligand (Anti-PD-1 and Anti-PD-L1). Certainly, the landscape of approved first line immunotherapeutic approaches has expanded to encompass monotherapy, immunotherapy-exclusive protocols, and combinations with chemotherapy. The complexity of decision-making in this realm arises due to the absence of direct prospective comparisons. However, a thorough analysis of the long-term efficacy and safety data derived from pivotal clinical trials can offer valuable insights into optimizing treatment for different patient subsets. Moreover, ongoing research is investigating emerging biomarkers and innovative therapeutic strategies that could potentially refine the current treatment approach even further. In this comprehensive review, our aim is to highlight the latest advances in immunotherapy for advanced NSCLC, including the mechanisms of action, efficacy, safety profiles, and clinical significance of ICI.

Radiation dose, schedule, and novel systemic targets for radio-immunotherapy combinations.

Immunotherapy combinations are being investigated to expand the benefit of immune checkpoint blockade across many cancer types. Radiation combinations, in particular using stereotactic body radiotherapy, are of keen interest because of underlying mechanistic rationale, safety, and availability as a standard of care in certain cancers. In addition to direct tumor cytotoxicity, radiation therapy has immunomodulatory effects such as induction of immunogenic cell death, enhancement of antigen presentation, and expansion of the T-cell receptor repertoire as well as recruitment and increased activity of tumor-specific effector CD8+ cells. Combinations of radiation with cytokines and/or chemokines and anti-programmed death 1 and anticytotoxic T-lymphocyte antigen 4 therapies have demonstrated safety and feasibility, as well as the potential to improve long-term outcomes and possibly induce out of irradiated field or abscopal responses. Novel immunoradiotherapy combinations represent a promising therapeutic approach to overcome radioresistance and further enhance systemic immunotherapy. Potential benefits include reversing CD8+ T-cell exhaustion, inhibiting myeloid-derived suppressor cells, and reversing M2 macrophage polarization as well as decreasing levels of colony-stimulating factor-1 and transforming growth factor-β. Here, we discuss current data and mechanistic rationale for combining novel immunotherapy agents with radiation therapy.

CCT6A and triple-negative breast cancer metastasis: Activating the AKT/MDM2/P53 pathway.

e13087 Background: Triple-negative breast cancer (TNBC) patients are prone to distant recurrence and poorer prognosis. The key molecules and underlying mechanisms of TNBC's aggressive phenotype remain to be further clarified. Methods: First, using the Kaplan-Meier Plotter ( https://kmplot.com/analysis ) and analyzing our collected clinical samples, we established the expression pattern and clinical value of the chaperonin containing TCP1 subunit 6A (CCT6A) in TNBC. We carried out the Cell Counting Kit-8 (CCK8), Transwell, and flow cytometry assay in the TNBC cell lines including MDA-MB-231 and BT549 to assess the effects of knockdown and overexpress of CCT6A. The mechanism of CCT6A in TNBC was identified by using the RNA-seq, KEGG analysis and Co-Immunoprecipitation Mass Spectrometry. Rescue assays verified the role of the AKT Serine/Threonine Kinase 1 (AKT) / Mouse double minute 2 homolog (MDM2)/P53 pathway on CCT6A. Then, the effect of CCT6A on tumor progression and metastasis in vivo was evaluated by the mouse models of tumorigenesis in situ and caudal artery lung metastasis. APG115, a pharmacological p53 activator and immune stimulatory MDM2 inhibitor, combined with anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody Ipilimumab was found to prevent TNBC metastasis. Finally, we did a profiling of the tumor immune environment in mice. Results: CCT6A was highly expressed in TNBC ( p<0.0001), and patients with high expression of CCT6A had poor prognosis ( p=0.0053, HR=2.36 [1.27-4.39]). Of note, CCT6A was significantly associated with lymph node metastasis ( p<0.0001). CCT6A promoted cell proliferation, migration, and invasion while inhibiting cell apoptosis and achieving G1/S stage arrest through gain- and loss-of-function approaches. In terms of mechanism, Co-IP and Immunofluorescence assay verified that CCT6A interacted with Keratin 10 (KRT10) which can promote tumor metastasis. Compared with the control group, RNA-seq, and KEGG analysis suggested that AKT/MDM2/P53 signaling was inhibited after knockdown of CCT6A in MDA-MB-231. Furthermore, we found that the tumor volume and the number of lung metastasis sites were significantly reduced in the APG115 combined with Ipilimumab treatment group. Flow cytometry and multiple Immunofluorescence assay showed that TGF-β level from regulatory T cells decreased, while IFN-γ amount from CD8+T cells significantly increased with the combination (both p<0.05). Conclusions: Our research demonstrated that CCT6A can enhance metastasis of triple-negative breast cancer via up-regulating the AKT/MDM2/P53 pathway. These results provide rationales for MDM2 inhibitor combined with anti-CTLA-4 antibody for preventing TNBC metastasis.

Tumour mutational burden as a biomarker in patients with mismatch repair deficient/microsatellite instability-high metastatic colorectal cancer treated with immune checkpoint inhibitors

BackgroundImmune checkpoint inhibitors (ICIs) are the standard treatment in patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). Tumour mutational burden (TMB) is a promising biomarker for the prediction of treatment outcomes. Patients and methodsWe screened 203 patients with dMMR/MSI-H mCRC treated with an anti-PD-(L)1 (anti-Programmed-Death-(Ligand)1) plus or minus an anti-Cytotoxic T-Lymphocyte Antigen 4 (anti-CTLA-4) agent at three Italian Academic Centers. TMB was tested by Foundation One Next Generation Sequencing assay and correlated with clinical outcomes, in the overall population and according to ICI regimen. ResultsWe included 110 patients with dMMR/MSI-H mCRC. Eighty patients received anti-PD-(L)1 monotherapy and 30 received anti-CTLA-4 combinations. Median TMB was 49 mut/Mb (range: 8–251 mut/Mb). The optimal prognostic cut-off for progression-free survival (PFS) stratification was 23 mut/Mb. Patients with TMB ≤23 mut/Mb had significantly worse PFS (adjusted Hazard Ratio [aHR] = 4.26, 95% confidence interval [CI]:1.85–9.82, p = 0.001) and overall survival (OS) (aHR = 5.14, 95% CI: 1.76–14.98, p = 0.003). Using a cut-off optimised for predicting treatment outcome, anti-CTLA-4 combination was associated with a significant PFS/OS benefit versus anti-PD-(L)1 monotherapy in patients with TMB>40 mut/Mb (2-year PFS: 100.0% versus 70.7%, p = 0.002; 2-year OS: 100.0% versus 76.0%, p = 0.025), but not in those with TMB ≤40 mut/Mb (2-year PFS: 59.7% versus 68.6%, p = 0.888; 2-year OS: 80.0% versus 81.0%, p = 0.949). ConclusionPatients with dMMR/MSI-H mCRC and relatively lower TMB value displayed early disease progression when receiving ICIs, whereas patients with the highest TMB values may obtain the maximal benefit from intensified anti-CTLA-4/PD-1 combination.

The impact of immunosuppressive agents on immune checkpoint inhibitor efficacy in patients with advanced melanoma: A real-world, multicenter, retrospective study.

Immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) are often managed via immunosuppressive agents (ISAs); however, their impact on ICI efficacy is not well studied. The impact of the use of ISAs on ICI efficacy in patients with advanced melanoma was therefore investigated. This is a real-world, multicenter, retrospective cohort study of patients with advanced melanoma who received ICIs (n=370). Overall survival (OS) and time to treatment failure (TTF) from the time of ICI initiation were compared among patients in subgroups of interest by unadjusted and 12-week landmark sensitivity-adjusted analyses. The association of irAEs and their management with OS and TTF were evaluated using univariate and multivariable Cox proportional hazards regression models. Overall, irAEs of any grade and of grade ≥3 occurred in 57% and 23% of patients, respectively. Thirty-seven percent of patients received steroids, and 3% received other ISAs. Median OS was longest among patients receiving both (not reached [NR]), shorter among those receiving only systemic steroids (SSs) (84.2months; 95% CI, 40.2 months to NR), and shortest among those who did not experience irAEs (10.3months; 95% CI, 6-20.1 months) (p<.001). Longer OS was significantly associated with the occurrence of irAEs and the use of SSs with or without ISAs upon multivariable-adjusted analysis (p<.001). Similar results were noted with anti-programmed death 1 (PD-1) monotherapy and combination anti-PD-1plusanti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) therapy, and with 12-week landmark sensitivity analysis (p=.01). These findings in patients with melanoma who were treated with ICIs suggest that the use of SSs or ISAs for the management of irAEs is not associated with inferior disease outcomes, which supports the use of these agents when necessary.

Oral Delivery of Therapeutic Antibodies with a Transmucosal Polymeric Carrier.

Therapeutic proteins are playing increasingly important roles in treating numerous types of diseases. However, oral administration of proteins, especially large ones (e.g., antibodies), remains a great challenge due to their difficulties in penetrating intestinal barriers. Herein, fluorocarbon-modified chitosan (FCS) is developed for efficient oral delivery of different therapeutic proteins, in particular large ones such as immune checkpoint blockade antibodies. In our design, therapeutic proteins are mixed with FCS to form nanoparticles, lyophilized with appropriate excipients, and then filled into enteric capsules for oral administration. It has been found that FCS could promote transmucosal delivery of its cargo protein via inducing transitory rearrangement of tight junction associated proteins between intestinal epithelial cells and subsequently release free proteins into blood circulation. It is shown that at a 5-fold dose oral delivery of anti-programmed cell death protein-1 (αPD1) or its combination with anti-cytotoxic T-lymphocyte antigen 4 (αCTLA4) using this method could achieve comparable antitumor therapeutic responses to that achieved by intravenous injection of corresponding free antibodies in various types of tumor models and, more excitingly, result in significantly reduced immune-related adverse events. Our work successfully demonstrates the enhanced oral delivery of antibody drugs to achieve systemic therapeutic responses and may revolutionize the future clinical usage of protein therapeutics.

Efficacy and safety of neoadjuvant immune checkpoint inhibitors in patients with localized mismatch repair deficient colorectal cancer: A systematic review.

149 Background: Clinical data demonstrating remarkable anti-tumor activity of immune checkpoint inhibitors (ICI) in patients with mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) and preclinical data suggesting enhanced efficacy of ICIs in the neoadjuvant setting than in the adjuvant setting led to numerous studies with neoadjuvant ICI in various tumor types including in dMMR CRC. We performed a systematic literature review of the published studies reporting the efficacy and safety of neoadjuvant ICIs in patients with localized dMMR CRC. Methods: Medline and Embase were searched for eligible case reports, case series, and clinical trial reports. Eligibility criteria included: 1. patients aged 18 years or older, 2. localized dMMR CRC, and 3. received neoadjuvant therapy primarily with ICI. Patients receiving radiation or chemotherapy along with ICI were excluded. The systematic review was conducted according to the PRISMA harms guidelines. Results: The database search yielded 143 citations which were reviewed by 3 authors (UG, KV, and SC), and 14 citations fulfilled all criteria for inclusion. The analysis included 173 patients with colon cancer (CC) and 19 with rectal cancer (RC). Among the patients with CC, 41 (24 %) received single-agent programmed death 1 (PD-1) blocker, and 132 (76 %) received dual blockade with an anti-PD-1 agent plus an anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) agent. Resection was performed in 171/173 (99%) patients, and 117/171 (69%) achieved complete pathological response (pCR). After median follow-up ranging between 8 and 15 months, none of the patients experienced cancer relapse. Among patients with RC, 16/19 (84%) received a PD-1 blocker, and 3 (16%) received dual PD-1 plus CTLA-4 blocker. Complete clinical response (cCR) was reported in 14/19 (74%) patients, and of the 5 patients who underwent surgery, 4 (80%) achieved pCR. All patients remained progression-free after median follow-up ranging from 6 to 12 months. Cancer progression or death on neoadjuvant ICI was not reported in any studies with CC or RC patients, and only two studies reported grade 3+ toxicity in 3% of CC patients. Conclusions: Neoadjuvant therapy with ICIs results in a remarkably high rate of clinical and pathological tumor regression with negligible safety concerns in patients with dMMR localized CRC. Well-designed clinical trials with long-term follow-up are needed to evaluate the organ-sparing potential of neoadjuvant ICI therapy in patients with dMMR CRC.

Analysis of Human Leukocyte Antigen DR Alleles, Immune-Related Adverse Events, and Survival Associated With Immune Checkpoint Inhibitor Use Among Patients With Advanced Malignant Melanoma

Treatment with immune checkpoint inhibitors (ICIs) has increased survival in patients with advanced malignant melanoma but can be associated with a wide range of immune-related adverse events (irAEs). The role of human leukocyte antigen (HLA)-DR alleles in conferring irAE risk has not been well studied. To evaluate the association between irAEs and treatment response, survival, and the presence of HLA-DR alleles after ICI therapy in advanced melanoma. This case-control study used the patient registry and biobanked samples from the tertiary referral University of Colorado Cancer Center. Specimens and clinical data were collected between January 1, 2010, and December 31, 2021. Patients with advanced (stage III unresectable and stage IV) melanoma who received ICI therapy (n = 132) were included in the analysis. Immune checkpoint inhibitors (anti-cytotoxic T-lymphocyte antigen 4, anti-programmed cell death protein 1 or its ligand, or the combination) for the treatment of advanced melanoma. The association between irAEs and response to therapy, survival, and HLA-DR alleles. Among the cohort of 132 patients with advanced melanoma (mean [SD] age, 63.4 [7.2] years; 85 men [64%] and 47 women [36%]) treated with ICIs, 73 patients had at least 1 irAE and 59 did not have an irAE. Compared with patients without an irAE, patients with an irAE had higher treatment response rates (50 of 72 [69%] vs 28 of 57 [49%]; P = .02) and increased survival (median, 4.8 [IQR, 0.2-9.6] vs 3.2 [IQR, 0.1-9.2] years; P = .02). Specific HLA-DR alleles were associated with the type of irAE that developed: 7 of 10 patients (70%) who developed type 1 diabetes had DR4; 6 of 12 (50%) who developed hypothyroidism had DR8; 5 of 8 (63%) who developed hypophysitis had DR15; 3 of 5 (60%) who developed pneumonitis had DR1; and 8 of 15 (53%) who developed hepatitis had DR4. These findings suggest that IrAEs are associated with treatment response rates and increased survival after ICI therapy for advanced melanoma. Because distinct HLA-DR alleles are associated with given adverse events, HLA genotyping before ICI therapy may aid in identifying risk for specific irAEs that could develop with such treatment.

Lung Cancer Immunotherapy: Beyond Common Immune Checkpoints Inhibitors.

Immunotherapy is an ever-expanding field in lung cancer treatment research. Over the past two decades, there has been significant progress in identifying immunotherapy targets and creating specific therapeutic agents, leading to a major paradigm shift in lung cancer treatment. However, despite the great success achieved with programmed death protein 1/ligand 1 (PD-1/PD-L1) monoclonal antibodies and with anti-PD-1/PD-L1 plus anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), only a minority of lung cancer patients respond to treatment, and of these many subsequently experience disease progression. In addition, immune-related adverse events sometimes can be life-threatening, especially when anti-CTLA-4 and anti-PD-1 are used in combination. All of this prompted researchers to identify novel immune checkpoints targets to overcome these limitations. Lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin (Ig) and Immunoreceptor Tyrosine-Based Inhibitory Motif (ITIM) domain (TIGIT), T cell immunoglobulin and mucin-domain containing-3 (TIM-3) are promising molecules now under investigation. This review aims to outline the current role of immunotherapy in lung cancer and to examine efficacy and future applications of the new immune regulating molecules.

Immune Checkpoint Inhibitors in Malignant Pleural Mesothelioma: A Systematic Review and Meta-Analysis.

Many clinical trials have investigated the role of ICIs in PM, with contrasting results. We performed a systematic review and meta-analysis of clinical trials testing single-agent anti-Programmed Death -1 (PD-1)/Programmed Death-Ligand 1 (PD-L1), anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) or combined treatment in PM patients, analyzing response and survival rate as well as safety data. We selected 17 studies including 2328 patients. Both OS and PFS rates were significantly higher with combined ICI treatments than with single agent anti-PD-1/PD-L1 (p &lt; 0.001 and p = 0.006, respectively) or anti CTLA-4 (p &lt; 0.001) treatments. ORR and DCR for all ICI treatments were 20% (95% CI 13-27%) and 56% (95% CI 45-67%), respectively, and they did not significantly differ between combined and single agent treatments (p = 0.088 and p = 0.058, respectively). The 12-month OS and 6-month PFS rates did not differ significantly (p = 0.0545 and p = 0.1464, respectively) among pre-treated or untreated patients. Combined ICI treatments had a significantly higher rate of Adverse Events (AEs) (p = 0.01). PD-L1-positive patients had a higher probability of response and survival. In conclusion, combined ICI treatments have higher efficacy than single agents but are limited by higher toxicity. Efficacy was independent of treatment line, so a customized sequential strategy should still be speculated. PD-L1 expression could influence response to ICIs; however, reliable biomarkers are warranted.

Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma

BackgroundImmune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in patients with advanced melanoma, but approximately half these patients will not have a durable benefit. Phase 1–2 trials of adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) have shown promising responses, but data from phase 3 trials are lacking to determine the role of TILs in treating advanced melanoma.MethodsIn this phase 3, multicenter, open-label trial, we randomly assigned patients with unresectable stage IIIC or IV melanoma in a 1:1 ratio to receive TIL or anti–cytotoxic T-lymphocyte antigen 4 therapy (ipilimumab at 3 mg per kilogram of body weight). Infusion of at least 5×109 TILs was preceded by nonmyeloablative, lymphodepleting chemotherapy (cyclophosphamide plus fludarabine) and followed by high-dose interleukin-2. The primary end point was progression-free survival.ResultsA total of 168 patients (86% with disease refractory to anti–programmed death 1 treatment) were assigned to receive TILs (84 patients) or ipilimumab (84 patients). In the intention-to-treat population, median progression-free survival was 7.2 months (95% confidence interval [CI], 4.2 to 13.1) in the TIL group and 3.1 months (95% CI, 3.0 to 4.3) in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; P<0.001); 49% (95% CI, 38 to 60) and 21% (95% CI, 13 to 32) of the patients, respectively, had an objective response. Median overall survival was 25.8 months (95% CI, 18.2 to not reached) in the TIL group and 18.9 months (95% CI, 13.8 to 32.6) in the ipilimumab group. Treatment-related adverse events of grade 3 or higher occurred in all patients who received TILs and in 57% of those who received ipilimumab; in the TIL group, these events were mainly chemotherapy-related myelosuppression.ConclusionsIn patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received ipilimumab. (Funded by the Dutch Cancer Society and others; ClinicalTrials.gov number, NCT02278887.)

New insight into GARP striking role in cancer progression: application for cancer therapy.

T regulatory cells play a crucial role in antitumor immunity suppression. Glycoprotein-A repetitions predominant (GARP), transmembrane cell surface marker, is mostly expressed on Tregs and mediates intracellular organization of transforming growth factor-beta (TGF-β). The physiological role of GARP is immune system homeostasis, while it may cause tumor development by upregulating TGF-β secretion. Despite the vast application of anti- programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) and anti-cytotoxic T-lymphocyte Antigen-4 (CTLA-4) antibodies in immunotherapy, anti-GARP antibodies have the advantage of better response in patients who has resistance to anti-PD-1/PD-L1. Furthermore, simultaneous administration of anti-GARP antibody and anti-PD-1/PD-L1 antibody is much more effective than anti-PD-1/PD-L1 alone. It is worth mentioning that the GARP-mTGF-β complex is more potent than secretory TGF-β to induce T helper 17 cells differentiation in HIV + patients. On the other hand, TGF-β is an effective cytokine in cancer development, and some microRNAs could control its secretion by regulating GARP. In the present review, some information is provided about the undeniable role of GARP in cancer progression and its probable importance as a novel prognostic biomarker. Anti-GARP antibodies are also suggested for cancer immunotherapy.

Elaborating on anti CTLA-4 mechanisms of action using an agent-based modeling approach

Anti CTLA-4 therapy is aimed at blocking the Cytotoxic T-lymphocyte antigen-4 (CTLA-4), a key cancer immunity cycle checkpoint. The mechanism of action of CTLA-4 may be described as a dynamic competition for the B7 ligand which, subsequently, interferes with the CD28-B7 costimulatory pathway. Anti CTLA-4 blockade enhances the process of cognate T cell activation and leads to a broadening of the T cell repertoire. In the present work, we used an agent-based modeling (ABM) platform of T cell immune response development, to explore hypothetical modes of anti CTLA-4 action. The model features a selected number of activated T cell clones, calculated based on combined random and chemotactically-driven encounters with antigen-presenting dendritic cells (DCs) and a distribution of individual T cell affinities to the antigen of interest. The proposed model can be used as a quantitative tool to explore various hypotheses on T cell immunity regulation and validate these against experimental data. A comprehensive ABM model analysis of immune response dynamic simulations revealed several putative anti CTLA-4 mechanisms of action, including: (i) an increase in the probability of primary activation of lymphocytes; (ii) T cell activation enhancement via a prolongation of short contacts with dendritic cells; and (iii) an increase in the maximum level of activation signal (or saturation), accumulated through a series of short contacts with DCs. The modeling work further demonstrates that it is only when considering jointly these various modes of anti CTLA-4 effects on the T cell immune response dynamics that a biologically meaningful increase in both the production of activated cells and the expansion of the T cell repertoire is observed. These model-based results are overall consistent with the collective biological knowledge on the functional role of CTLA-4. Furthermore, the ABM presented here may allow to interrogate various mechanistic scenarios underlying adverse events mediated by anti CTLA-4 pharmacologic therapies.