bims-tuinly 2024-09-29 papers

bims-tuinly

Biomed News

on Tumor-infiltrating lymphocytes therapy

Issue of 2024–09–29
eight papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Patient-derived xenografts and single-cell sequencing identifies three subtypes of tumor-reactive lymphocytes in uveal melanoma metastases.
Recent advancements in improving the efficacy and safety of chimeric antigen receptor (CAR)-T cell therapy for hepatocellular carcinoma.
Recent advances and progress in immunotherapy of solid cancers.
The NSCLC immunotherapy response predicted by tumor-infiltrating T cells via a non-invasive radiomic approach.
Emerging Cancer Immunotherapies: Cutting-Edge Advances and Innovations in Development.
Regulatory T lymphocytes as a treatment method for rheumatoid arthritis - Superiority of allogeneic to autologous cells.
Development of a Predictive Model for Emergency Department Utilization and Unanticipated Hospital Admission in Patients Receiving Cancer Treatment for Solid Tumor Malignancies.
Chimeric Antigen Receptor T Cells Targeting CD19 and GCC in Metastatic Colorectal Cancer: A Nonrandomized Clinical Trial.

Elife. 2024 Sep 23. pii: RP91705. [Epub ahead of print]12

Patient-derived xenografts and single-cell sequencing identifies three subtypes of tumor-reactive lymphocytes in uveal melanoma metastases.

Joakim W Karlsson, Vasu R Sah, Roger Olofsson Bagge, Irina Kuznetsova, Munir Iqba, Samuel Alsen, Sofia Stenqvist, Alka Saxena, Lars Ny, Lisa M Nilsson, Jonas A Nilsson.

  Uveal melanoma (UM) is a rare melanoma originating in the eye's uvea, with 50% of patients experiencing metastasis predominantly in the liver. In contrast to cutaneous melanoma, there is only a limited effectiveness of combined immune checkpoint therapies, and half of patients with uveal melanoma metastases succumb to disease within 2 years. This study aimed to provide a path toward enhancing immunotherapy efficacy by identifying and functionally validating tumor-reactive T cells in liver metastases of patients with UM. We employed single-cell RNA-seq of biopsies and tumor-infiltrating lymphocytes (TILs) to identify potential tumor-reactive T cells. Patient-derived xenograft (PDX) models of UM metastases were created from patients, and tumor sphere cultures were generated from these models for co-culture with autologous or MART1-specific HLA-matched allogenic TILs. Activated T cells were subjected to TCR-seq, and the TCRs were matched to those found in single-cell sequencing data from biopsies, expanded TILs, and in livers or spleens of PDX models injected with TILs. Our findings revealed that tumor-reactive T cells resided not only among activated and exhausted subsets of T cells, but also in a subset of cytotoxic effector cells. In conclusion, combining single-cell sequencing and functional analysis provides valuable insights into which T cells in UM may be useful for cell therapy amplification and marker selection.

Keywords:  cancer biology; cellular immunotherapy; genetics; genomics; human; mouse; patient-derived xenograft; tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.7554/eLife.91705
Naunyn Schmiedebergs Arch Pharmacol. 2024 Sep 24.

Recent advancements in improving the efficacy and safety of chimeric antigen receptor (CAR)-T cell therapy for hepatocellular carcinoma.

Tuo Ren, Yonghui Huang.

  The liver is one of the most frequent sites of primary malignancies in humans. Hepatocellular carcinoma (HCC) is one of the most prevalent solid tumors with poor prognosis. Current treatments showed limited efficacy in some patients, and, therefore, alternative strategies, such as immunotherapy, cancer vaccines, adoptive cell therapy (ACT), and recently chimeric antigen receptors (CAR)-T cells, are developed to offer better efficacy and safety profile in patients with HCC. Unlike other ACTs like tumor-infiltrating lymphocytes (TILs), CAR-T cells are equipped with engineered CAR receptors that effectively identify tumor antigens and eliminate cancer cells without major histocompatibility complex (MHC) restriction. This process induces intracellular signaling, leading to T lymphocyte recruitment and subsequent activation of other effector cells in the tumor microenvironment (TME). Until today, novel approaches have been used to develop more potent CAR-T cells with robust persistence, specificity, trafficking, and safety. However, the clinical application of CAR-T cells in solid tumors is still challenging. Therefore, this study aims to review the advancement, prospects, and possible avenues of CAR-T cell application in HCC following an outline of the CAR structure and function.

Keywords:  Adoptive cell therapy; CAR-T cell; Hepatocellular carcinoma; Immunotherapy

DOI:  https://doi.org/10.1007/s00210-024-03443-7
Adv Cancer Res. 2024 ;pii: S0065-230X(24)00014-9. [Epub ahead of print]164 111-190

Recent advances and progress in immunotherapy of solid cancers.

Amit Kumar, Luni Emdad, Swadesh K Das, Paul B Fisher.

  Adoptive cell therapy using chimeric antigen receptor (CAR) technology has become mainstream by employing advanced engineering platforms to promote cancer immunotherapy. CAR T cells have shown remarkable efficacy in the treatment of hematological malignancies; however, the value of this therapy remains inconclusive in the context of solid tumors. Immunotherapy of solid tumors is restrained by several obstacles including the presence of an immunosuppressive tumor microenvironment (TME), limited tumor trafficking, inhibited immune cell infiltration, absence of tumor-specific antigens, and off-target toxicity and adverse events associated with these therapies. Despite recent advances in CAR T cell construction, including the integration of co-stimulatory domains and the creation of armed CAR T cells, with promising outcomes in the treatment of some solid tumors, there are still many unresolved obstacles that need to be overcome. To surmount these impediments to effective CAR T cell therapies, other immune cells, such as natural killer cells and macrophages, have been engineered to serve as appealing alternatives for successful cancer immunotherapy of solid tumors. CAR NK cells demonstrate significant clinical advantages due to their ready availability and minimal toxicity. CAR macrophage (M) cells provide considerable therapeutic potential due to their ability to penetrate the TME of solid tumors. In this review, we comprehensively examine the latest developments and prospects of engineered immune cell-based cancer immunotherapies specifically designed for treating solid tumors. In addition, we provide a concise overview of current clinical trials that are examining the safety and effectiveness of modified immune cells, such as CAR T, CAR NK, and CAR M, in their ability to specifically target solid tumors and promote improved therapeutic outcomes in patients with diverse solid cancers.

Keywords:  CAR NK cells; CAR T cells; CAR macrophages; Immunotherapy; Solid cancers

DOI:  https://doi.org/10.1016/bs.acr.2024.05.004
Front Immunol. 2024 ;15 1379812

The NSCLC immunotherapy response predicted by tumor-infiltrating T cells via a non-invasive radiomic approach.

Jie Min, Fei Dong, Yongyuan Chen, Wenshan Li, Yimin Wu, Yanbin Tan, Fan Yang, Pin Wu, Ying Chai.

   Introductions: Identifying patients with non-small cell lung cancer (NSCLC) who are optimal candidates for immunotherapy is a cornerstone in clinical decision-making. The tumor immune microenvironment (TIME) is intricately linked with both the prognosis of the malignancy and the efficacy of immunotherapeutic interventions. CD8+ T cells, and more specifically, tissue-resident memory CD8+ T cells [CD8+ tissue-resident memory T (TRM) cells] are postulated to be pivotal in orchestrating the immune system's assault on tumor cells. Nevertheless, the accurate quantification of immune cell infiltration-and by extension, the prediction of immunotherapeutic efficacy-remains a significant scientific frontier.
Methods: In this study, we introduce a cutting-edge non-invasive radiomic model, grounded in TIME markers (CD3+ T, CD8+ T, and CD8+ TRM cells), to infer the levels of immune cell infiltration in NSCLC patients receiving immune checkpoint inhibitors and ultimately predict their response to immunotherapy. Data from patients who had surgical resections (cohort 1) were employed to construct a radiomic model capable of predicting the TIME. This model was then applied to forecast the TIME for patients under immunotherapy (cohort 2). Conclusively, the study delved into the association between the predicted TIME from the radiomic model and the immunotherapeutic outcomes of the patients.
Result: For the immune cell infiltration radiomic prediction models in cohort 1, the AUC values achieved 0.765, 0.763, and 0.675 in the test set of CD3+ T, CD8+ T, and CD8+ TRM, respectively. While the AUC values for the TIME-immunotherapy predictive value were 0.651, 0.763, and 0.829 in the CD3-immunotherapy response model, CD8-immunotherapy response model, and CD8+ TRM-immunotherapy response model in cohort 2, respectively. The CD8+ TRM-immunotherapy model exhibited the highest predictive value and was significantly better than the CD3-immunotherapy model in predicting the immunotherapy response. The progression-free survival (PFS) analysis based on the predicted levels of CD3+ T, CD8+ T, and CD8+ TRM immune cell infiltration showed that the CD8+ T cell infiltration level was an independent factor (P=0.014, HR=0.218) with an AUC value of 0.938.
Discussion: Our empirical evidence reveals that patients with substantial CD8+ T cell infiltration experience a markedly improved PFS compared with those with minimal infiltration, asserting the status of the CD8+ T cell as an independent prognosticator of PFS in the context of immunotherapy. Although CD8+ TRM cells demonstrated the greatest predictive accuracy for immunotherapy response, their predictive strength for PFS was marginally surpassed by that of CD8+ T cells. These insights advocate for the application of the proposed non-invasive radiomic model, which utilizes TIME analysis, as a reliable predictor for immunotherapy outcomes and PFS in NSCLC patients.

Keywords:  immune checkpoint inhibitors; immunotherapy; non-small cell lung cancer; radiomic; tumor immune microenvironment

DOI:  https://doi.org/10.3389/fimmu.2024.1379812
Med Sci (Basel). 2024 Aug 28. pii: 43. [Epub ahead of print]12(3):

Emerging Cancer Immunotherapies: Cutting-Edge Advances and Innovations in Development.

Monica Maccagno, Marta Tapparo, Gabriele Saccu, Letizia Rumiano, Sharad Kholia, Lorenzo Silengo, Maria Beatriz Herrera Sanchez.

  The rise in biological therapies has revolutionized oncology, with immunotherapy leading the charge through breakthroughs such as CAR-T cell therapy for melanoma and B-ALL. Modified bispecific antibodies and CAR-T cells are being developed to enhance their effectiveness further. However, CAR-T cell therapy currently relies on a costly ex vivo manufacturing process, necessitating alternative strategies to overcome this bottleneck. Targeted in vivo viral transduction offers a promising avenue but remains under-optimized. Additionally, novel approaches are emerging, such as in vivo vaccine boosting of CAR-T cells to strengthen the immune response against tumors, and dendritic cell-based vaccines are under investigation. Beyond CAR-T cells, mRNA therapeutics represent another promising avenue. Targeted delivery of DNA/RNA using lipid nanoparticles (LNPs) shows potential, as LNPs can be directed to T cells. Moreover, CRISPR editing has demonstrated the ability to precisely edit the genome, enhancing the effector function and persistence of synthetic T cells. Enveloped delivery vehicles packaging Cas9 directed to modified T cells offer a virus-free method for safe and effective molecule release. While this platform still relies on ex vivo transduction, using cells from healthy donors or induced pluripotent stem cells can reduce costs, simplify manufacturing, and expand treatment to patients with low-quality T cells. The use of allogeneic CAR-T cells in cancer has gained attraction for its potential to lower costs and broaden accessibility. This review emphasizes critical strategies for improving the selectivity and efficacy of immunotherapies, paving the way for a more targeted and successful fight against cancer.

Keywords:  CAR-T; CRISPR/Cas9; LNPs; cancer; cell therapy; immunotherapy; vaccine

DOI:  https://doi.org/10.3390/medsci12030043
Heliyon. 2024 Sep 15. 10(17): e36512

Regulatory T lymphocytes as a treatment method for rheumatoid arthritis - Superiority of allogeneic to autologous cells.

Joanna Chmiel, Mariusz Stasiak, Maria Skrzypkowska, Lucjan Samson, Piotr Łuczkiewicz, Piotr Trzonkowski.

  Cellular therapies utilizing regulatory T cells (Tregs) have flourished in the autoimmunity space as a new pillar of medicine. These cells have shown a great promise in the treatment of such devastating conditions as type 1 diabetes mellitus (T1DM), systemic lupus erythematosus (SLE) and graft versus host disease (GVHD). Novel treatment protocols, which utilize Tregs-mediated suppressive mechanisms, are based on the two main strategies: administration of immunomodulatory factors affecting Tregs or adoptive cell transfer (ACT). ACT involves extraction, in vitro expansion and subsequent administration of Tregs that could be either of autologous or allogeneic origin. Rheumatoid arthritis (RA) is another autoimmune candidate where this treatment approach is being considered. RA remains an especially challenging adversary since it is one of the most frequent and debilitating conditions among all autoaggressive disorders. Noteworthy, Tregs circulating in RA patients' blood have been proven defective and unable to suppress inflammation and joint destruction. With this knowledge, adoptive transfer of compromised autologous Tregs in the fledgling clinical trials involving RA patients should be reconsidered. In this article we hypothesize that incorporation of healthy donor allogeneic Tregs may provide more lucid and beneficial results.

Keywords:  Adoptive cell therapy (ACT); Regulatory T cells (tregs); Rheumatoid arthritis (RA)

DOI:  https://doi.org/10.1016/j.heliyon.2024.e36512
JCO Oncol Pract. 2024 Sep 20. OP2300571

Development of a Predictive Model for Emergency Department Utilization and Unanticipated Hospital Admission in Patients Receiving Cancer Treatment for Solid Tumor Malignancies.

Catherine H Watson, Brooke Alhanti, Congwen Zhao, Laura J Havrilesky, Brittany A Davidson.

PURPOSE: Unanticipated health care resource utilization, in the form of either emergency department utilization (EDU) or hospital admission (HA), may be an indicator of lower-quality cancer care. The objective of this study was to develop a predictive model for EDU and HAs within 14 days of receipt of systemic therapy for patients with solid tumors.
METHODS: We abstracted electronic health data on oncology encounters from all patients receiving systemic therapy for solid tumors from March 1, 2015, to August 21, 2020, in the Duke University Health System. We defined a primary composite outcome of an EDU or HA within 14 days after the encounter and then developed a predictive model for the primary outcome using least absolute shrinkage and selection operator regression. To evaluate the model, we calculated the area under the receiver operator curve and the calibration slope.
RESULTS: Twelve thousand eight hundred ninety unique patients with 134,641 oncology encounters were included. Five thousand one hundred fifty of these patients (40.0%) had at least one EDU or HA within 14 days of at least one treatment. Forty-six variables were incorporated into the final model. The top predictors, in order of absolute value of the predictive coefficients, were temperature, systolic blood pressure, cancer group, and marital status. The model's AUC was 0.73 (95% CI, 0.722 to 0.732), indicating good sensitivity and specificity to outcome.
CONCLUSION: The model developed in this study demonstrated good sensitivity in identifying patients with solid tumors who are at highest risk for EDU or HA and could be implemented in clinical practice to allow for preventive outpatient interventions.

DOI: https://doi.org/10.1200/OP.23.00571
JAMA Oncol. 2024 Sep 19.

Chimeric Antigen Receptor T Cells Targeting CD19 and GCC in Metastatic Colorectal Cancer: A Nonrandomized Clinical Trial.

Naifei Chen, Chengfei Pu, Lingling Zhao, Wei Li, Chang Wang, Ruihong Zhu, Tingting Liang, Chao Niu, Xi Huang, Haiyang Tang, Yizhuo Wang, Hang Yang, Beibei Jia, Xianyang Jiang, Guiting Han, Wensheng Wang, Dongqi Chen, Yiming Wang, Eric K Rowinsky, Eugene Kennedy, Victor X Lu, Guozhen Cui, Zhao Wu, Lei Xiao, Jiuwei Cui.

Importance: Chimeric antigen receptor (CAR) T-cell therapy (CART) has transformed the treatment landscape of hematologic cancer, but has negligible effects for adult solid cancers. In this trial, an autologous CAR T-cell product demonstrated antitumor activity in heavily pretreated patients with metastatic colorectal cancer (mCRC).
Objective: To evaluate the safety and efficacy of guanylate cyclase-C (GCC19) CART in participants with metastatic colorectal cancer (mCRC).
Design, Setting, and Participants: This single-arm, nonrandomized, phase 1 trial was conducted at the First Hospital of Jilin University from December 3, 2020, to April 13, 2022. Data analysis was conducted from May 2022 to April 2024. Adults with relapsed and refractory mCRC expressing GCC were treated with GCC19CART, a mixture of autologous CAR T cells transduced with lentiviral vectors expressing genes that encode either CD-19 CAR or GCC CAR.
Main Outcomes and Measures: Safety and tolerability of CAR T-cell therapy targeting GCC in patients with mCRC without therapeutic options is capable of conferring a reasonable likeliness of clinical benefit. Other outcomes included objective response rate, progression-free survival, overall survival, and immune activation.
Results: Of 15 patients 9 (60%) were women, and the median (range) age was 44 (33-61) years. Treatment with GCC19CART was associated with the development of cytokine release syndrome and diarrhea in most patients, all of which were self-limited and manageable. The objective response rate was 40%, with a partial response in 2 of 8 and 4 of 7 patients treated with either 1 × 106 cells/kg or 2 × 106 cells/kg. Median overall survival was 22.8 months (95% CI, 13.4-26.1) at data cutoff; the median progress-free survival was 6.0 months in the high dose level group (95% CI, 3.0 to not available).
Conclusions and Relevance: The results of this nonrandomized clinical trial suggest that GCC19CART was safe and tolerable in heavily pretreated patients with mCRC and is the first CAR T-cell therapy known to produce objective clinical activity in refractory cancer. Given the paucity of effective therapeutics developed for colorectal cancer in recent decades, the observation that CD-19 CART target engagement can robustly induce GCC19CART target engagement sufficient to produce objective activity may serve as a foundation to develop effective cellular therapy in mCRC and other solid cancers.
Trial Registration: Chinese Clinical Trial Registry: ChiCTR2000040645.

DOI: https://doi.org/10.1001/jamaoncol.2024.3891