Mediate Tumor Regression Research Articles

Vax-Innate: improving therapeutic cancer vaccines by modulating T cells and the tumour microenvironment.

T cells have a critical role in mediating antitumour immunity. The success of immune checkpoint inhibitors (ICIs) for cancer treatment highlights how enhancing endogenous T cell responses can mediate tumour regression. However, mortality remains high for many cancers, especially in the metastatic setting. Based on advances in thegenetic characterization of tumours and identification of tumour-specific antigens, individualized therapeutic cancer vaccines targeting mutated tumour antigens (neoantigens) are being developed to generate tumour-specific T cells for improved therapeutic responses. Early clinical trials using individualized neoantigen vaccines for patients with advanced disease had limited clinical efficacy despite demonstrated induction of T cell responses. Therefore, enhancing T cell activity by improving the magnitude, quality and breadth of T cell responses following vaccination is one current goal for improving outcome against metastatic tumours. Another major consideration is how T cells can be further optimized to function within the tumour microenvironment (TME). In this Perspective, we focus on neoantigen vaccines and propose a new approach, termed Vax-Innate, in which vaccination through intravenous delivery or in combination with tumour-targeting immune modulators may improve antitumour efficacy by simultaneously increasing the magnitude, quality and breadth of T cells while transforming the TME into a largely immunostimulatory environment for T cells.

MAP kinase kinase 1 (MEK1) within extracellular vesicles inhibits tumour growth by promoting anti-tumour immunity.

Extracellular vesicles (EVs) mediate intercellular communication in many physiologic processes and can modulate immune responses in individuals with cancer. Most studies of EVs in cancer have focused on their tumour promoting properties. Whether and how EVs might mediate tumour regression besides carrying antigens has not been well characterized. Using a mouse model of highly immunogenic regressor versus poorly immunogenic progressor tumour cells, we have characterized the role of EVs in activating macrophages and promoting tumour rejection. We found that the signalling molecule MAP2K1 (MEK1) is enriched in EVs secreted by regressor relative to progressor cells. Progressor EVs engineered to have levels of MEK1 similar to regressor EVs could inhibit tumour growth by indirectly promoting adaptive immunity in both syngeneic and 3rd party tumours. This effect required MEK1 activity and could occur by activating macrophages to promote adaptive immune responses against the tumour via the cytokine interferon-gamma. Our results suggest that MEK inhibition may be deleterious to cancer treatment, since MEK1 plays an important cell-extrinsic, tumour-suppressive role within EVs. Moreover, the delivery of MEK1 to tumour-associated macrophages, either by EVs, nanoparticles, or some other means, could be a useful strategy to treat cancer via the activation of anti-tumour immunity.

Adoptive transfer of personalized neoantigen-reactive TCR-transduced T cells in metastatic colorectal cancer: phase 2 trial interim results.

Adoptive cell transfer (ACT) with neoantigen-reactive T lymphocytes can mediate cancer regression. Here we isolated unique, personalized, neoantigen-reactive T cell receptors (TCRs) from tumor-infiltrating lymphocytes of patients with metastatic gastrointestinal cancers and incorporated the TCR α and β chains into gamma retroviral vectors. We transduced autologous peripheral blood lymphocytes and adoptively transferred these cells into patients after lymphodepleting chemotherapy. In a phase 2 single-arm study, we treated seven patients with metastatic, mismatch repair-proficient colorectal cancers who had progressive disease following multiple previous therapies. The primary end point of the study was the objective response rate as measured using RECIST 1.1, and the secondary end points were safety and tolerability. There was no prespecified interim analysis defined in this study. Three patients had objective clinical responses by RECIST criteria including regressions of metastases to the liver, lungs and lymph nodes lasting 4 to 7 months. All patients received T cell populations containing ≥50% TCR-transduced cells, and all T cell populations were polyfunctional in that they secreted IFNγ, GM-CSF, IL-2 and granzyme B specifically in response to mutant peptides compared with wild-type counterparts. TCR-transduced cells were detected in the peripheral blood of five patients, including the three responders, at levels ≥10% of CD3+ cells 1 month post-ACT. In one patient who responded to therapy, ~20% of CD3+ peripheral blood lymphocytes expressed transduced TCRs more than 2 years after treatment. This study provides early results suggesting that ACT with T cells genetically modified to express personalized neoantigen-reactive TCRs can be tolerated and can mediate tumor regression in patients with metastatic colorectal cancers. ClinicalTrials.gov registration: NCT03412877 .

Paclitaxel and cisplatin/carboplatin plus tislelizumab in young patients with cervical cancer preserve fertility: Phase II prospective, single arm clinical study.

e17513 Background: Cervical function damage after fertility-sparing surgery has a lower pregnancy success rate. Chemotherapy (chemo) mainly plays an auxiliary role in the treatment of cervical cancer (CC), but its efficacy is limited. Recently, immunotherapy has shown remarkable progress in treatment of CC, potentially provide new treatment options for pts of childbearing age who require preservation of fertility. Herein, we conducted this study to evaluate the efficacy and safety of chemo plus tislelizumab (TIS) in young pts with CC who required fertility preservation. Methods: In this single arm, phase II trial, pts with histologically confirmed invasive, FIGO2018 stage IB1-IB3 or IIIC1r (localized cervical lesions) CC, and having fertility needs were enrolled. Eligible pts received 4 cycles chemo (175 mg/m2 paclitaxel + 70 mg/m2 cisplatin/AUC 5-6 carboplatin, Q3W) + TIS (200 mg, Q3W), followed by surgery-diagnostic cervical conization and sentinel lymph node (SLN) biopsy (IIIC1r stage with pelvic lymph node [PLN] systematic dissection)-upon achieving a radiographic complete response (CR). After surgery, pts will undergo 2-cycle chemo plus TIS therapy, if PLNs achieve a pathological complete response (pCR), regardless of the pCR status of localized cervical lesion. If the first cervical conization did not result in a pCR for localized cervical lesion only, a second conization was performed after 2-cycle chemo + TIS. Upon achieving pCR in both the cervical local disease and PLN, maintenance therapy (MT) with TIS will be continued for 1 year. Primary endpoint is pCR (SLN/PLNs + cervical conization) after surgery. The key secondary endpoints included clinical response to 4 cycles chemo + TIS, pregnancy rate, fertility rate, and treatment-emergent adverse events (TEAEs). Results: Between March 2022 and January 2024, 7 pts (mean age 31 years, range 27-38) were enrolled, with 2 pts (28.6%) having stage IIIC1r disease. All 7 pts received chemo plus TIS therapy; of these, 5 (71.4%) pts completed 4 cycles The objective response was achieved in 5 pts, with all complete response. Amenorrhea was observed in 3 of 5 pts (60%), with 2 recovering normal menstruation after chemo cessation, and 1 had finished the last chemo+TIS for 3 weeks and had not yet returned. During 4 cycles chemo + TIS therapy (n=7), the most common TEAEs of any grade were rash (71.4%), alanine aminotransferase increased (57.1%), neutrophil count decreased (57.1%), and white blood cell count decreased (57.1%). At data cutoff (median follow-up, 9 months, range 3.5-17), 1 pt experienced disease progression during MT, and 1 pt got pregnancy 3 months after completed MT. Conclusions: Chemo plus TIS could mediate tumor regression and eliminate micro-metastases with a tolerable safety profile, potentially allowing for fertility preservation in many pts for which this was not thought to be an option. Clinical trial information: ChiCTR2300067495.

PD-1-CD28-enhanced receptor and CD19 CAR-modified tumor-infiltrating T lymphocytes produce potential anti-tumor ability in solid tumors

The limited expansion ability and functional inactivation of T cells within the solid tumor microenvironment are major problems faced during in the application of using tumor-infiltrating lymphocytes (TILs) in vivo. We sought to determine whether TILs carrying a PD-1-CD28-enhanced receptor and CD19 CAR could overcome this limitation and mediate tumor regression. First, anti-tumor effects of PD-1-CD28-enhanced receptor or CD19 CAR modified NY-ESO-1-TCR-T cells to mimic the TILs function (hereafter “PD-1-CD28-TCR-T” or “CD19 CAR-TCR-T” cells, respectively) were tested using the NY-ESO-1 over-expressed tumor cell line in vitro and in a tumor-bearing model. Furthermore, the safety and anti-tumor ability of S-TILs (TILs modified through transduction with a plasmid encoding the PD-1-CD28-T2A-CD19 CAR) were evaluated in vivo. PD-1-CD28-TCR-T cells showed a formidable anti-tumor ability that was not subject to PD-1/PD-L1 signaling in vivo. CD19 CAR-TCR-T cells stimulated with CD19+ B cells exhibited powerful expansion and anti-tumor abilities both in vitro and in vivo. Three patients with refractory solid tumors received S-TILs infusion. No treatment-related mortality was observed, and none of the patients experienced serious side effects. One patient with melanoma achieved a partial response, and two patients with colon or kidney cancer achieved long-term stable disease following S-TILs therapy. To the best of our knowledge, this is the first study describing the safety and efficacy of the adoptive transfer of autologous S-TILs to control disease in patients with advanced cancers, suggesting that S-TILs may be a promising alternative therapy for cancer.

Preclinical evaluation of two phylogenetically distant arenavirus vectors for the development of novel immunotherapeutic combination strategies for cancer treatment

BackgroundEngineered arenavirus vectors have recently been developed to leverage the body’s immune system in the fight against chronic viral infections and cancer. Vectors based on Pichinde virus (artPICV) and lymphocytic...

Abstract 4092: Characterizing the endogenous retroviral envelope protein ERVMER34-1 as a target for a therapeutic cancer vaccine

Abstract Endogenous retroviruses (ERVs) are remnants of retroviral germline infections which occurred over the course of evolution and constitute between 5-8% of the human genome. Although ERV protein expression is typically silenced epigenetically in normal adult human tissues, previous studies have shown that some ERVSs, can be aberrantly expressed in multiple cancer types. This atypical expression of ERVs in tumors may represent a class of immunologically relevant tumor-associated antigens that can potentially be targeted clinically using therapeutic cancer vaccines. For the first time, this study evaluates the ERV envelope protein ERVMER34-1 as a potential target for a therapeutic cancer vaccine. We first assessed the expression of ERVMER34-1 in multiple tissues and found that ERVMER34-1 protein is absent in most healthy adult tissues and over expressed in multiple types of human carcinomas. ERVMER34-1 specific T-cells were detected in PBMCs of cancer patients but not healthy donors following an overnight stimulation. However, reactive T-cells are readily expanded from both healthy donor and cancer patient PBMCs following a 7-day in-vitro stimulation. Importantly, reactive CD8+ T cells selectively killed human carcinoma cells expressing the target antigen. Based on these findings, we rationally designed a ERVMER34-1 therapeutic cancer vaccine and assessed its immunogenicity and anti-tumor efficacy in established syngeneic murine tumors expressing the full-length ERVMER34-1 protein. Our rationally designed ERVMER34-1 cancer vaccine significantly mediated tumor regression and extended survival as a monotherapy and in combination with checkpoint blockade. Altogether, our work supports the clinical development of a therapeutic cancer vaccine targeting the retroviral envelope protein ERVMER34-1 as a potential first-in-class immunotherapeutic target for the therapy of several carcinoma types. Citation Format: Maria Del Mar Maldonado, Masafumi Iida, Maria Del Mar Gracia Hernandez, Loc Le, Renee N. Donahue, Claudia Palena, Jeffrey Schlom, Duane H. Hamilton. Characterizing the endogenous retroviral envelope protein ERVMER34-1 as a target for a therapeutic cancer vaccine [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 4092.

An EBV-related CD4 TCR immunotherapy inhibits tumor growth in an HLA-DP5+ nasopharyngeal cancer mouse model.

Adoptive transfer of T cell receptor-engineered T cells (TCR-T) is a promising strategy for immunotherapy against solid tumors. However, the potential of CD4+ T cells in mediating tumor regression has been neglected. Nasopharyngeal cancer is consistently associated with EBV. Here, to evaluate the therapeutic potential of CD4 TCR-T in nasopharyngeal cancer, we screened for CD4 TCRs recognizing EBV nuclear antigen 1 (EBNA1) presented by HLA-DP5. Using mass spectrometry, we identified EBNA1567-581, a peptide naturally processed and presented by HLA-DP5. We isolated TCR135, a CD4 TCR with high functional avidity, that can function in both CD4+ and CD8+ T cells and recognizes HLA-DP5-restricted EBNA1567-581. TCR135-transduced T cells functioned in two ways: directly killing HLA-DP5+EBNA1+ tumor cells after recognizing EBNA1 presented by tumor cells and indirectly killing HLA-DP5-negative tumor cells after recognizing EBNA1 presented by antigen-presenting cells. TCR135-transduced T cells preferentially infiltrated into the tumor microenvironment and significantly inhibited tumor growth in xenograft nasopharyngeal tumor models. Additionally, we found that 62% of nasopharyngeal cancer patients showed 50%-100% expression of HLA-DP on tumor cells, indicating that nasopharyngeal cancer is well suited for CD4 TCR-T therapy. These findings suggest that TCR135 may provide a new strategy for EBV-related nasopharyngeal cancer immunotherapy in HLA-DP5+ patients.

Role of Natural Killer T (NKT) Cells in Myeloma Biology and Therapy.

Natural Killer T (NKT) cells are distinct innate lymphocytes that recognize lipid antigens in the context of nonpolymorphic molecule CD1d. Multiple myeloma (MM) is a hematologic malignancy wherein malignant plasma cells express CD1d and are sensitive to lysis by NKT cells. Progressive malignancy in MM is characterized by NKT cell dysfunction. Several studies have tried to harness the anti-tumor properties of NKT cells in MM to mediate tumor regression. NKT cells are also attractive targets for approaches at immune redirection in MM with chimeric-antigen receptor NKT (CAR-NKT) and bispecific antibodies. In addition to the commonly studied invariant-NKT (iNKT) cells, MM patients often also exhibit alterations in type-II NKT cells and their ligands. In patients and mouse models with Gaucher disease (GD), an inherited lipid-storage disorder with markedly increased risk for MM, distinct type-II NKT cells exhibit a T-follicular helper (NKT-TFH) phenotype and provide help to lipid-specific B cells. Chronic immune activation in this setting eventually sets the stage for malignancy, which can be targeted in both mouse models and GD patients by reducing the underlying antigen. NKT cells are thus integrally linked to MM pathogenesis and an attractive target for MM immunotherapy.

Overcoming Resistance Mechanisms to Immune Checkpoint Inhibitors: Leveraging the Anti-Tumor Immune Response.

As far back as 3000 years ago, the immune system was observed to play a role in mediating tumor regression. Since then, many strategies have been developed to leverage the anti-tumor immune response. However, while many patients respond to ICIs up front some do not, and many of those that do eventually experience tumor progression. Currently, there are several predictive biomarkers of the immune checkpoint inhibitor response; however, no one test appears to be universally predictive and their application varies by disease site. There are many ways in which cancer cells develop primary or acquired resistance to immune checkpoint inhibitors. Efforts to reverse resistance include ways to combat T cell exhaustion, reprogram the tumor microenvironment, increase the availability of tumor neo-antigens, target alternative immune checkpoints, restore a normal/healthy patient gut microbiome, oncolytic viruses and tumor vaccines. The most studied and most promising methods include combining ICIs with therapies targeting alternative immune checkpoints and restoring a normal/healthy patient gut microbiome. This review will discuss T cell-mediated immunity, how this is leveraged by modern immunotherapy to treat cancer and mechanisms of immune checkpoint inhibitor resistance, while highlighting strategies to overcome primary and secondary resistance mechanisms.

Albendazole induces an anti-tumor effect and potentiates PD-L1 blockade immunotherapy.

Previously, albendazole (ABZ) has been reported as an anti-parasitic drug rather than anti-tumor drug. Our study aim to investigate whether ABZ also has a potential anti-tumor effect by shaping the tumor immune microenvironment and interrogate whether ABZ could synergize with the PD-L1 blockade. C57BL/6 mice (C57) were intravenously injected with B16F10-luciferase (B16-luc) cells to establish a lung metastatic melanoma model and subcutaneously inoculated with B16-luc cells to establish a subcutaneous tumor model. The tumor volume and tumor metastasis loci of the mice were measured by a vernier caliper and in vivo imaging. RNA sequencing was performed to analyze the different genes and pathways of immune cells in the tumors. Flow cytometry and immunofluorescence were used to analyze the different subsets of tumor-infiltrating immune cells. The results suggested that ABZ significantly inhibited lung melanoma metastasis with decreased fluorescence intensity and nodule score and mediated the regression of subcutaneous melanoma in mice with decreased tumor volume. Moreover, RNA sequencing results showed that ABZ regulated the gene expression levels and pathways of immune cells in the tumor microenvironment (TME). Meanwhile, flow cytometry and immunofluorescence showed that the number and percentage of CD8+ T cells, CD4+ T cells, and TH1 cells were enhanced in tumors after ABZ treatment. Furthermore, the combination of ABZ and anti-PD-L1 treatment significantly potentiated anti-tumor efficacy in both lung metastasis and subcutaneous melanoma models and mediated an increase in the percentage of CD8+ T cells, CD4+ T cells, and TH1 cells as compared to the control group. ABZ inhibits melanoma growth and metastasis. Moreover, ABZ synergized with PD-L1 blockade mediates tumor regression.

HDACi-dependent Microenvironmental Normalization Overcomes Tumor Burden-induced T-cell Exhaustion.

T-cell exhaustion limits immunotherapy for the treatment of solid tumors. Although immune checkpoint blockade and adoptive T-cell therapy (ACT) can mediate tumor regression, their potency is often determined by tumor burden. Here, we identified tumor burden-related pathway changes that are conducive to T-cell exhaustion. We then determined whether microenvironmental reprogramming via epigenetic modulation could reverse T-cell exhaustion and improve immunotherapeutic responsiveness. We developed a murine syngeneic tumor model wherein an increased burden ablated therapeutic responsiveness to ACT, which corresponded with systemic induction of T-cell exhaustion. Transcriptome analysis of these large tumors allowed us to characterize changes to immunosuppressive pathway expression during class I histone deacetylase inhibitor MS-275 treatment. We then measured the therapeutic impact of MS-275 during ACT and assessed T-cell exhaustion by transcriptome/phenotypic analysis. ACT durably regressed small tumors but failed to control large tumors, which were associated with systemic T-cell exhaustion and ablation of T-cell responses. Large tumors were defined by an immunosuppressive pathway signature. MS-275 reversed this pathway signature and promoted durable regression of large tumors during ACT. Prototypical exhaustion marker Tim-3 was selectively upregulated in transferred T cells despite displaying a reduced exhaustion signature. Instead, we observed enhanced activation-dependent signaling correlating with enrichment of the IL2-STAT5 signaling axis. Activated CD8+ T-cell responses were predominantly skewed toward terminal effector cell-like CD44+ Tim-3hi TCF1- CD127- KLRG1+ differentiation. Tumor burden-induced pathway changes can be reversed through epigenetic reprogramming, enabling the conversion from T-cell exhaustion to effector lineage differentiation.

METTL3 drives NAFLD-related hepatocellular carcinoma and is a therapeutic target for boosting immunotherapy

Non-alcoholic fatty liver disease (NAFLD) is an emerging risk factor of hepatocellular carcinoma (HCC). However, the mechanism and target therapy of NAFLD-HCC are still unclear. Here, we identify that the N6-methyladenosine (m6A) methyltransferase METTL3 promotes NAFLD-HCC. Hepatocyte-specific Mettl3 knockin exacerbated NAFLD-HCC formation, while Mettl3 knockout exerted the opposite effect in mice. Single-cell RNA sequencing revealed that METTL3 suppressed antitumor immune response by reducing granzyme B (GZMB+) and interferon gamma-positive (IFN-γ+) CD8+ Tcell infiltration, thereby facilitating immune escape. Mechanistically, METTL3 mediates sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) mRNA m6A to promote its translation, leading to the activation of cholesterol biosynthesis. This enhanced secretion of cholesterol and cholesteryl esters that impair CD8+ Tcell function in the tumor microenvironment. Targeting METTL3 by single-guide RNA, nanoparticle small interfering RNA (siRNA), or pharmacological inhibitor (STM2457) in combination with anti-programmed cell death protein 1 (PD-1) synergized to reinvigorate cytotoxic CD8+ Tcells and mediate tumor regression. Together, METTL3 is a therapeutic target in NAFLD-HCC, especially in conjunction with immune checkpoint blockade (ICB) therapy.

Intravenous heterologous prime-boost vaccination activates innate and adaptive immunity to promote tumor regression

Therapeutic neoantigen cancer vaccines have limited clinical efficacy to date. Here, we identify a heterologous prime-boost vaccination strategy using a self-assembling peptide nanoparticle TLR-7/8 agonist (SNP) vaccine prime and a chimp adenovirus (ChAdOx1) vaccine boost that elicits potent CD8 Tcells and tumor regression. ChAdOx1 administered intravenously (i.v.) had 4-fold higher antigen-specific CD8 Tcell responses than mice boosted by the intramuscular (i.m.) route. In the therapeutic MC38 tumor model, i.v. heterologous prime-boost vaccination enhances regression compared with ChAdOx1 alone. Remarkably, i.v. boosting with a ChAdOx1 vector encoding an irrelevant antigen also mediates tumor regression, which is dependent on type I IFN signaling. Single-cell RNA sequencing of the tumor myeloid compartment shows that i.v. ChAdOx1 reduces the frequency of immunosuppressive Chil3 monocytes and activates cross-presenting type 1 conventional dendritic cells (cDC1s). The dual effect of i.v. ChAdOx1 vaccination enhancing CD8 Tcells and modulating the TME represents a translatable paradigm for enhancing anti-tumor immunity in humans.

Phase I results of human endogenous retrovirus type-E (HERV-E) TCR transduced T-cells in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC).

2549 Background: The CT-RCC HERV-E is expressed in the majority of ccRCC tumors with no expression in normal tissues. T-cells transduced to express a HERV-E TCR are cytotoxic to ccRCC & mediate tumor regression of human ccRCC in a murine model. We developed a method to manufacture HERV-E TCR transduced T-cells (HERV-E TCR) for clinical development. Methods: We conducted a phase I dose-escalation trial (DL1:1x106, DL2:5x106, DL3:1x107 & DL4:5x107cells/kg) to evaluate the safety of adoptively infused HERV-E TCR in mccRCC pts. HERV-E TCR contain T-cells engineered to express an HLA-A*11 restricted HERV-E TCR and a truncated CD34 cassette for in vivo monitoring. Eligible HLA-A*11 pts had mccRCC, ECOG 0-1 & prior antiangiogenic & checkpoint inhibitors therapy unless contraindicated/unavailable. Cyclophosphamide & fludarabine were given followed by HERV-E TCR infusion & IL-2 administration. Results: 14 HLA-A*11+ pts (median age 56) were treated including 3 pts in each DLs 1-3 & 5 pts in DL4. 86% had ≥ 3 prior treatment lines (range 1-7): 36% had high-dose IL2, 57% Ipilimumab-Nivolumab & 50% ≥ 3 lines of anti-VEGFR therapy. Bone, liver & brain metastases were present in 71%, 43%, and 14% of pts. All HERV-E TCR products met sterility, purity, and potency criteria for release and infusion (Table). No HERV-E TCR dose-limiting toxicities or treatment-related deaths occurred. Pts received a mean: 12 IL-2 doses (IQR 11-14). 57% pts had G3-4 febrile neutropenia & 7% G3-4 capillary leak syndrome. 1 pt experienced G2 skin rash possibly related to HERV-E TCR. Best response included 7% pts with partial response & 29% with stable disease ≥ 8 weeks. The mPFS: 62 days (IQR 31,90). At DL4, TCR transgene expression was detectable in PBMCs at a mean 6.3% (range (r) 0.02-25), 12.3% (r 0.01-61.2), 3.45% (r 0.00-13.7) & 2.89% (r 0.00-11.5) on days 4, 7, 14, & 21. HERV-E TCR were detected in the malignant pleural effusion of 1 pt. Conclusions: This is the first trial evaluating TCR-engineered T-cells targeting a human endogenous retrovirus in ccRCC. The manufacturing method utilized produced large numbers of highly purified CD8+ HERV-E reactive T-cells that were not associated with any dose limiting toxicities when given at doses up to 5x107 cells/kg. For pts in DL4, HERV-E TCR were observed to proliferate in vivo, traffic to a metastatic site, and induce tumor regression in one mccRCC pts. Clinical trial information: NCT03354390 . [Table: see text]

Current application of immunotherapy in melanoma.

Current application of immunotherapy in melanoma.

Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab.

Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued. Patients with advanced melanoma (N = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation. Median overall survival in nivolumab-treated patients (62% with two to five prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. Among 33 patients with objective tumor regressions (31%), the Kaplan-Meier estimated median response duration was 2 years. Seventeen patients discontinued therapy for reasons other than disease progression, and 12 (71%) of 17 maintained responses off-therapy for at least 16 weeks (range, 16 to 56+ weeks). Objective response and toxicity rates were similar to those reported previously; in an extended analysis of all 306 patients treated on this trial (including those with other cancer types), exposure-adjusted toxicity rates were not cumulative. Overall survival following nivolumab treatment in patients with advanced treatment-refractory melanoma compares favorably with that in literature studies of similar patient populations. Responses were durable and persisted after drug discontinuation. Long-term safety was acceptable. Ongoing randomized clinical trials will further assess the impact of nivolumab therapy on overall survival in patients with metastatic melanoma.

Identification of a CD4+ conventional T cells-related lncRNAs signature associated with hepatocellular carcinoma prognosis, therapy, and tumor microenvironment.

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, and CD4+ T lymphocytes can inhibit hepatocarcinogenesis and mediate tumor regression. However, few studies have focused on the prognostic power of CD4+ Tconv-related lncRNAs in HCC patients. We obtained data from TCGA and GEO databases and identified CD4+Tconv-related lncRNAs in HCC. The risk score was constructed using lasso regression and the model was validated using two validation cohorts. The RS was also assessed in different clinical subgroups, and a nomogram was established to further predict the patients' outcomes. Furthermore, we estimated the immune cell infiltration and cancer-associated fibroblasts (CAFs) through TIMER databases and assessed the role of RS in immune checkpoint inhibitors response. We constructed a CD4+ Tconv-related lncRNAs risk score, including six lncRNAs (AC012073.1, AL031985.3, LINC01060, MKLN1-AS, MSC-AS1, and TMCC1-AS1), and the RS had good predictive ability in validation cohorts and most clinical subgroups. The RS and the T stage were included in the nomogram with optimum prediction and the model had comparable OS prediction power compared to the AJCC. Patients in the high-risk group had a poor immune response phenotype, with high infiltrations of macrophages, CAFs, and low infiltrations of NK cells. Immunotherapy and chemotherapy response analysis indicated that low-risk group patients had good reactions to immune checkpoint inhibitors. We constructed and validated a novel CD4+ Tconv-related lncRNAs RS, with the potential predictive value of HCC patients' survival and immunotherapy response.

Expansion of KRAS hotspot mutations reactive T cells from human pancreatic tumors using autologous T cells as the antigen-presenting cells.

Adoptive cell therapy (ACT) with expanded tumor-infiltrating lymphocytes (TIL) or TCR gene-modified T cells (TCR-T) that recognize mutant KRAS neo-antigens can mediate tumor regression in patients with advanced pancreatic ductal adenocarcinoma (PDAC) (Tran et al in N Engl J Med, 375:2255-2262, 2016; Leidner et al in N Engl J Med, 386:2112-2119, 2022). The mutant KRAS-targeted ACT holds great potential to achieve durable clinical responses for PDAC, which has had no meaningful improvement over 40years. However, the wide application of mutant KRAS-centric ACT is currently limited by the rarity of TIL that recognize the mutant KRAS. In addition, PDAC is generally recognized as a poorly immunogenic tumor, and TILs in PDAC are less abundant than in immunogenic tumors such as melanoma. To increase the success rate of TIL production, we adopted a well-utilized K562-based artificial APC (aAPC) that expresses 4-1BBL as the costimulatory molecules to enhance the TIL production from PDCA. However, stimulation with K562-based aAPC led to a rapid loss of specificity to mutant KRAS. To selectively expand neo-antigen-specific T cells, particularly mKRAS, from the TILs, we used tandem mini gene-modified autologous T cells (TMG-T) as the novel aAPC. Using this modified IVS protocol, we successfully generated TIL cultures specifically reactive to mKRAS (G12V). We believe that autologous TMG-T cells provide a reliable source of autologous APC to expand a rare population of neoantigen-specific T cells in TILs.

Systemic vaccination induces CD8+ T cells and remodels the tumor microenvironment

Therapeutic cancer vaccines are designed to increase tumor-specific Tcell immunity. However, suppressive mechanisms within the tumor microenvironment (TME) may limit Tcell function. Here, we assessed how the route of vaccination alters intratumoral myeloid cells. Using a self-assembling nanoparticle vaccine that links tumor antigen peptides to a Toll-like receptor 7/8 agonist (SNP-7/8a), we treated tumor-bearing mice subcutaneously (SNP-SC) or intravenously (SNP-IV). Both routes generated antigen-specific CD8+ Tcells that infiltrated tumors. However, only SNP-IV mediated tumor regression, dependent on systemic type I interferon at the time of boost. Single-cell RNA-sequencing revealed that intratumoral monocytes expressing an immunoregulatory gene signature (Chil3, Anxa2, Wfdc17) were reduced after SNP-IV boost. In humans, the Chil3+ monocyte gene signature is enriched in CD16- monocytes and associated with worse outcomes. Our results show that the generation of tumor-specific CD8+ Tcells combined with remodeling of the TME is a promising approach for tumor immunotherapy.