Radiotherapy (RT) is the standard-of-care treatment for more than half of cancer patients with localized tumors and is also used as palliative care to facilitate symptom relief in metastatic cancers. ...In addition, RT can alter the immunosuppressive tumor microenvironment (TME) of solid tumors to augment the anti-tumor immune response of immune checkpoint blockade (ICB). The rationale of this combination therapy can also be extended to other forms of immunotherapy, such as chimeric antigen receptor T cell (CAR-T) therapy. Similar to ICB, the efficacy of CAR-T therapy is also significantly impacted by the immunosuppressive TME, leading to compromised T cell function and/or insufficient T cell infiltration. In this review, we will discuss some of the key barriers to the activity of CAR-T cells in the immunosuppressive TME and focus on how RT can be used to eliminate or bypass these barriers. We will present the challenges to achieving success with this therapeutic partnership. Looking forward, we will also provide strategies currently being investigated to ensure the success of this combination strategy in the clinic.
Mucosal-associated invariant T (MAIT) cells are T cells that recognise vitamin-B derivative Ag presented by the MHC-related-protein 1 (MR1) antigen-presenting molecule. While MAIT cells are highly ...abundant in humans, their role in tumour immunity remains unknown. Here we have analysed the frequency and function of MAIT cells in multiple myeloma (MM) patients. We show that MAIT cell frequency in blood is reduced compared to healthy adult donors, but comparable to elderly healthy control donors. Furthermore, there was no evidence that MAIT cells accumulated at the disease site (bone marrow) of these patients. Newly diagnosed MM patient MAIT cells had reduced IFNγ production and CD27 expression, suggesting an exhausted phenotype, although IFNγ-producing capacity is restored in relapsed/refractory patient samples. Moreover, immunomodulatory drugs Lenalidomide and Pomalidomide, indirectly inhibited MAIT cell activation. We further show that cell lines can be pulsed with vitamin-B derivative Ags and that these can be presented via MR1 to MAIT cells in vitro, to induce cytotoxic activity comparable to that of natural killer (NK) cells. Thus, MAIT cells are reduced in MM patients, which may contribute to disease in these individuals, and moreover, MAIT cells may represent new immunotherapeutic targets for treatment of MM and other malignancies.
Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) are an approved treatment for hormone receptor-positive breast cancer and are currently under evaluation across hundreds of ...clinical trials for other cancer types. The clinical success of these inhibitors is largely attributed to well-defined tumor-intrinsic cytostatic mechanisms, whereas their emerging role as immunomodulatory agents is less understood. Using integrated epigenomic, transcriptomic, and proteomic analyses, we demonstrated a novel action of CDK4/6 inhibitors in promoting the phenotypic and functional acquisition of immunologic T-cell memory. Short-term priming with a CDK4/6 inhibitor promoted long-term endogenous antitumor T-cell immunity in mice, enhanced the persistence and therapeutic efficacy of chimeric antigen receptor T cells, and induced a retinoblastoma-dependent T-cell phenotype supportive of favorable responses to immune checkpoint blockade in patients with melanoma. Together, these mechanistic insights significantly broaden the prospective utility of CDK4/6 inhibitors as clinical tools to boost antitumor T-cell immunity. SIGNIFICANCE: Immunologic memory is critical for sustained antitumor immunity. Our discovery that CDK4/6 inhibitors drive T-cell memory fate commitment sheds new light on their clinical activity, which is essential for the design of clinical trial protocols incorporating these agents, particularly in combination with immunotherapy, for the treatment of cancer.
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This study explored the novel immune checkpoint poliovirus receptor-related immunoglobulin domain-containing (PVRIG) in acute myeloid leukemia (AML). We showed that AML patient blasts consistently ...expressed the PVRIG ligand (poliovirus receptor-related 2, PVRL2). Furthermore, PVRIG blockade significantly enhanced NK cell killing of PVRL2+, poliovirus receptor (PVR)lo AML cell lines, and significantly increased NK cell activation and degranulation in the context of patient primary AML blasts. However, in AML patient bone marrow, NK cell PVRIG expression levels were not increased. To understand how PVRIG blockade might potentially be exploited therapeutically, we investigated the biology of PVRIG and revealed that NK cell activation resulted in reduced PVRIG expression on the cell surface. This occurred whether NK cells were activated by tumour cell recognition, cytokines (IL-2 and IL-12) or activating receptor stimulation (CD16 and NKp46). PVRIG was present at higher levels in the cytoplasm than on the cell surface, particularly on CD56bright NK cells, which further increased cytoplasmic PVRIG levels following IL-2 and IL-12 activation. PVRIG was continually transported to the cell surface via the endoplasmic reticulum (ER) and Golgi in both unstimulated and activated NK cells. Taken together, our findings suggest that anti- PVRIG blocking antibody functions by binding to surface-bound PVRIG, which undergoes rapid turnover in both unstimulated and activated NK cells. We conclude that the PVRIGPVRL2 immune checkpoint axis can feasibly be targeted with PVRIG blocking antibody for NK-mediated immunotherapy of PVRL2+ AML.
Chimeric antigen receptor (CAR) T cell therapy has been highly successful in hematological malignancies leading to their US Food and Drug Administration (FDA) approval. However, the efficacy of CAR ...T cells in solid tumors is limited by tumor-induced immunosuppression, leading to the development of combination approaches, such as adjuvant programmed cell death 1 (PD-1) blockade. Current FDA-approved methods for generating CAR T cells utilize either anti-CD3 and interleukin (IL)-2 or anti-CD3/CD28 beads, which can generate a T cell product with an effector/exhausted phenotype. Whereas different cytokine preconditioning milieu, such as IL-7/IL-15, have been shown to promote T cell engraftment, the impact of this approach on CAR T cell responses to adjuvant immune-checkpoint blockade has not been assessed. In the current study, we reveal that the preconditioning of CAR T cells with IL-7/IL-15 increased CAR T cell responses to anti-PD-1 adjuvant therapy. This was associated with the emergence of an intratumoral CD8+CD62L+TCF7+IRF4– population that was highly responsive to anti-PD-1 therapy and mediated the vast majority of transcriptional and epigenetic changes in vivo following PD-1 blockade. Our data indicate that preservation of CAR T cells in a TCF7+ phenotype is crucial for their responsiveness to adjuvant immunotherapy approaches and should be a key consideration when designing clinical protocols.
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Group 2 innate lymphoid cells (ILC2s) are essential to maintain tissue homeostasis. In cancer, ILC2s can harbor both pro-tumorigenic and anti-tumorigenic functions, but we know little about their ...underlying mechanisms or whether they could be clinically relevant or targeted to improve patient outcomes. Here, we found that high ILC2 infiltration in human melanoma was associated with a good clinical prognosis. ILC2s are critical producers of the cytokine granulocyte-macrophage colony-stimulating factor, which coordinates the recruitment and activation of eosinophils to enhance antitumor responses. Tumor-infiltrating ILC2s expressed programmed cell death protein-1, which limited their intratumoral accumulation, proliferation and antitumor effector functions. This inhibition could be overcome in vivo by combining interleukin-33-driven ILC2 activation with programmed cell death protein-1 blockade to significantly increase antitumor responses. Together, our results identified ILC2s as a critical immune cell type involved in melanoma immunity and revealed a potential synergistic approach to harness ILC2 function for antitumor immunotherapies.
Immune profiling of pediatric solid tumors Terry, Rachael L; Meyran, Deborah; Ziegler, David S ...
The Journal of clinical investigation,
07/2020, Letnik:
130, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Pediatric cancers, particularly high-risk solid tumors, urgently need effective and specific therapies. Their outlook has not appreciably improved in decades. Immunotherapies such as immune ...checkpoint inhibitors offer much promise, but most are only approved for use in adults. Though several hundred clinical trials have tested immune-based approaches in childhood cancers, few have been guided by biomarkers or clinical-grade assays developed to predict patient response and, ultimately, to help select those most likely to benefit. There is extensive evidence in adults to show that immune profiling has substantial predictive value, but few studies focus on childhood tumors, because of the relatively small disease population and restricted use of immune-based therapies. For instance, only one published study has retrospectively examined the immune profiles of pediatric brain tumors after immunotherapy. Furthermore, application and integration of advanced multiplex techniques has been extremely limited. Here, we review the current status of immune profiling of pediatric solid tumors, with emphasis on tumor types that represent enormous unmet clinical need, primarily in the context of immune checkpoint inhibitor therapy. Translating optimized and informative immune profiling into standard practice and access to personalized combination therapy will be critical if childhood cancers are to be treated effectively and affordably.
Highlights • Tumor microenvironment limits the effectiveness of ACT. • New strategies to genetically manipulate T cells to modulate cytokine networks have the potential to reprogram the tumor ...microenvironment. • Novel strategies for enhancing the activation and survival of adoptively transferred T cells may increase anti-tumor effects. • Combination of ACT and checkpoint blockade therapy is likely to broaden the scope of immunotherapy in the clinical setting.
In men with high prostate-specific membrane antigen (PSMA)-expressing, high-risk localised prostate cancer, upfront lutetium PSMA before radical prostatectomy delivers high doses of targeted ...radiation to sites of tumour. It is well tolerated, and surgery after Lu-PSMA treatment is straightforward and safe. This warrants further research to determine oncologic benefit before clinical implementation.
High-risk localised prostate cancer (HRCaP) has high rates of biochemical recurrence; 177LuLu-PSMA-617 is effective in men with advanced prostate cancer.
To investigate the dosimetry, safety, and efficacy of upfront 177LuLu-PSMA-617 in men with HRCaP prior to robotic radical prostatectomy (RP).
In this single-arm, phase I/II trial, we recruited men with HRCaP (any of prostate-specific antigen PSA >20 ng/ml, International Society of Urological Pathology (ISUP) grade group GG 3–5, and ≥cT2c), with high tumour uptake on 68GaGa-PSMA-11 positron emission tomography/computed tomography (PSMA PET/CT), and scheduled for RP.
Cohort A (n = 10) received one cycle and cohort B (n = 10) received two cycles of 177LuLu-PSMA-617 (5 GBq) followed by surgery 6 weeks later.
The primary endpoint was tumour radiation absorbed dose. Adverse events (AEs; Common Terminology Criteria for Adverse Events (CTCAE) version 5.0), surgical safety (Clavien-Dindo), imaging, and biochemical responses were evaluated (ClinicalTrials.gov: NCT04430192).
Between May 29, 2020 and April 28, 2022, 20 patients were enrolled. The median PSA was 18 ng/ml (interquartile range IQR 11–35), Eighteen (90%) had GG ≥3, and six (30%) had N1 disease. The median (IQR) highest tumour radiation absorbed dose after cycle 1 for all lesions was 35.5 Gy (19.5–50.1), with 19.6 Gy (11.3–48.4) delivered to the prostate. Five patients received radiation to lymph nodes. Nine (45%) patients achieved >50% PSA decline. The most common AEs related to 177LuLu-PSMA-617 were grade 1 fatigue in eight (40%), nausea in seven (35%), dry mouth in six (30%), and thrombocytopenia in four (20%) patients. No grade 3/4 toxicities or Clavien 3–5 complications occurred. Limitations include small a sample size.
In men with HRCaP and high prostate-specific membrane antigen (PSMA) expression, 177LuLu-PSMA-617 delivered high levels of targeted radiation doses with few toxicities and without compromising surgical safety. Further studies of 177LuLu-PSMA-617 in this population are worthwhile to determine whether meaningful long-term oncological benefits can be demonstrated.
In this study, we demonstrate that up to two cycles of 177LuLu-PSMA-617 given prior to radical prostatectomy in patients with high-risk localised prostate cancer are safe and deliver targeted doses of radiation to tumour-affected tissues. It is tolerated well with minimal treatment-related adverse events, and surgery is safe with a low rate of complications. Activity measured through PSA reduction, repeat PSMA PET/CT, and histological response is promising.
CD8+ tumor-infiltrating lymphocytes with a tissue-resident memory T (TRM) cell phenotype are associated with favorable prognosis in patients with triple-negative breast cancer (TNBC). However, the ...relative contribution of CD8+ TRM cells to anti-tumor immunity and immune checkpoint blockade efficacy in breast cancer remains unknown. Here, we show that intratumoral CD8+ T cells in murine mammary tumors transcriptionally resemble those from TNBC patients. Phenotypic and transcriptional studies established two intratumoral sub-populations: one more enriched in markers of terminal exhaustion (TEX-like) and the other with a bona fide resident phenotype (TRM-like). Treatment with anti-PD-1 and anti-CTLA-4 therapy resulted in expansion of these intratumoral populations, with the TRM-like subset displaying significantly enhanced cytotoxic capacity. TRM-like CD8+ T cells could also provide local immune protection against tumor rechallenge and a TRM gene signature extracted from tumor-free tissue was significantly associated with improved clinical outcomes in TNBC patients treated with checkpoint inhibitors.
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•Intratumoral CD8+ T cells in murine TNBC consist of both TEX-like and TRM-like cells•Dual-ICB therapy augments and enhances the killing capacity of TRM-like cells•CD8+ TRM-like cells provide local tissue protection from TNBC tumor rechallenge•CD8+ TRM signature is associated with better treatment outcomes in TNBC patients
Virassamy et al. characterize the qualitative features of intratumoral CD8+ T cells and the critical role of T cells displaying residency properties (TRM) in mouse models of triple-negative breast cancer (TNBC). TRM cells expand in response to anti-PD-1 and anti-CTLA-4 immune checkpoint inhibition and confer ongoing tissue protective immunity against TNBC.
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