A phase I study to evaluate the T-cell engager AMV564 alone and in combination with pembrolizumab in subjects with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3101-3101
Author(s):  
Alexander Starodub ◽  
Sarina Anne Piha-Paul ◽  
Raghad Karim ◽  
Curtis Ruegg ◽  
Victoria Smith ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Cell Activation ◽  
Gastroesophageal Junction ◽  
Effector Memory ◽  
Cytotoxic T Cell ◽  
Advanced Solid Tumors

3101 Background: Overcoming the immune-suppressive tumor environment induced by myeloid-derived suppressor cells (MDSC) is a major challenge in immune therapy. CD33 signaling in immature myeloid cells promotes expansion of MDSC and production of immune-suppressive factors. AMV564 is a bivalent, bispecific T-cell engager that binds CD3 and CD33. Preferential binding of AMV564 to areas of high CD33 density enables selective targeting of MDSC. Ex vivo data (Cheng 2017; Blood;130:51) and an ongoing clinical trial in acute myeloid leukemia (NCT03144245) demonstrate the ability of AMV564 to deplete MDSC while sparing monocytes and neutrophils. Methods: In this 3+3 dose escalation study, patients with advanced solid tumors receive AMV564 once daily via subcutaneous (SC) injection for 2 out of 3 wks per cycle, alone or in combination with pembrolizumab (200 mg every 3 wks). Key objectives are to evaluate AMV564 safety, identify a maximum tolerated or recommended phase 2 dose, and evaluate PK, immunophenotype of myeloid and T cell compartments, and preliminary efficacy. Results: Eleven patients have been enrolled: 8 monotherapy (3 at 15 mcg/d, 5 at 50 mcg/d) and 3 combination (5 mcg/d). Tumor types include ovarian (n = 2), small bowel, gastroesophageal junction, endometrial, rectal, penile, urothelial, squamous cell carcinoma (skin), appendiceal, and non-small cell lung. AMV564 was associated with grade (G) 1-2 injection site reactions and G1-2 fevers, which were manageable with acetaminophen and diphenhydramine, as well as G2 weight gain and G3 anemia. No dose-liming toxicity has been observed in any cohort. Three monotherapy patients (15 mcg/d) were evaluable for efficacy with ≥1 on-treatment scan; 2 had SD and 1 PD per RECIST 1.1 criteria. T cell activation, as shown by redistribution from the periphery (margination), was apparent in the first week of dosing for most patients. Compensatory myelopoiesis led to initial expansion of MDSC which were then depleted by AMV564. Increased cytotoxic T cell activation and T-helper (Th) 1 response was evidenced by increased T-bet positive CD4 and CD8 cells and controlled or decreased regulatory T cells. In some patients, effector memory CD8 cell populations (Tem and Temra) were expanded. Conclusions: AMV564 is safe and tolerable when administered SC at doses of 15 mcg/d alone and 5 mcg/d in combination with pembrolizumab. AMV564 depleted MDSC populations and altered T cell profiles consistent with activation of cytotoxic T cells and a Th1 response. Clinical trial information: NCT04128423 .

A phase I dose escalation (DE) and cohort expansion (CE) study of ERY974, an anti-glypican 3 (GPC3)/CD3 bispecific antibody, in patients with advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3112-TPS3112
Author(s):  
Kenji Hashimoto ◽  
Ayesh Perera ◽  
Naofumi Sugaya ◽  
Yoshitaka Ogita ◽  
Mikiko Nakamura ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Dose Escalation ◽  
Cell Activation ◽  
Bispecific Antibody ◽  
Gastroesophageal Junction ◽  
Occurrence Rate ◽  
Cytotoxic T Cell ◽  
Therapy Strategy

TPS3112 Background: Bispecific antibodies to facilitate T-cell directed cytotoxicity (TDCC) is a proven therapy strategy in cancer. ERY974 is a humanized IgG4 bispecific antibody designed to simultaneously bind to cytotoxic T-cell CD3 receptors and GPC3 (a glycoprotein expressed on cell surface of several tumors) to elicit T-cell activation and TDCC. The objectives of this multi-country, phase 1 study of ERY974 is to determine the maximum tolerated dose (MTD) and to perform a preliminary assessment of anti-tumor activity in patients with solid tumors expressing GPC3. Methods: ERY974 is dosed IV weekly. All patients receive premedication with dexamethasone (DEX) prior to 1st and 2nd ERY974 dose. DE uses an accelerated titration design (ATD), then a modified continual reassessment method (mCRM) described by one-parameter logistic model, to determine MTD, where DLT occurrence rate is 0.25. Combining ATD and mCRM is to permit rapid dose escalation whilst minimizing patient numbers exposed to sub-therapeutic doses, and to accurately determine MTD. Once grade 2 (G2) cytokine release syndrome (CRS) is observed, DEX is increased. If ≥G2 CRS is again observed, then at all subsequent doses the 1st dose of ERY974 is fixed at the last dose level when < G2 CRS was not seen, DE proceeds with the 2nd dose. ATD commences with n = 1, increasing to n = 3 once drug-related ≥G2 toxicity is seen. mCRM starts after 1st dose limiting toxicity (DLT), with the modifications of at least 3 patients required to dose escalate and up to 1.5x increment to minimize risk of toxicity. CE has 3 arms: GPC3+ gastric/gastroesophageal junction adenocarcinoma; GPC3+ squamous esophageal cancer; and other GPC3+ tumors. A 2-stage design is used to allow CE to stop early for futility. Subjects are adults with histologically confirmed, measurable malignant solid tumors and/or metastatic disease not amenable to standard therapy, and life expectancy ≥3 months. Patients with > 1cm or > 1 brain metastasis, current/previous interstitial lung disease, and acute/chronic infection are excluded. 3 cohorts have been completed without DLT. Cohort 4 began in January 2017. Clinical trial information: NCT02748837.

Parasite species regulates T cell activation in human malaria

2021 ◽  
Author(s):  
Florian Bach ◽  
Diana Munoz Sandoval ◽  
Michalina Mazurczyk ◽  
Yrene Themistocleous ◽  
Thomas A Rawlinson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Plasmodium Vivax ◽  
T Cell Activation ◽  
Cell Activation ◽  
Parasite Species ◽  
Field Isolate ◽  
Effector Memory ◽  
Lymphoid Tissues ◽  
Systems Immunology

Plasmodium vivax offers unique challenges for malaria control and may prove a more difficult species to eradicate than Plasmodium falciparum. Yet compared to P. falciparum we know very little about the innate and adaptive immune responses that need to be harnessed to reduce disease and transmission. In this study, we inoculated human volunteers with a clonal field isolate of P. vivax and used systems immunology tools to track their response through infection and convalescence. Our data reveal Plasmodium vivax triggers an acute phase response that shares remarkable overlap with that of P. falciparum, suggesting a hardwired innate response that does not differentiate between parasite species. This leads to the global recruitment of innate-like and adaptive T cells into lymphoid tissues where up to one quarter of the T cell compartment is activated. Heterogeneous effector memory-like CD4+ T cells dominate this response and their activation coincides with collateral tissue damage. Remarkably, comparative transcriptional analyses show that P. falciparum drives even higher levels of T cell activation; diverging T cell responses may therefore explain why falciparum malaria more frequently causes severe disease.

scholarly journals 368 Consistent pattern of immune activation induced by oncolytic adenovirus ONCOS-102 across diverse types of solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A396-A396
Author(s):  
Lukasz Kuryk ◽  
Anne-Sophie Moller ◽  
Sandeep Kumar ◽  
Alexander Shoushtari ◽  
Luis Paz Ares ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Clinical Importance ◽  
Oncolytic Adenovirus ◽  
Link Type ◽  
Tumor Types

BackgroundSolid tumors exhibit highly variable compositions of immune infiltrates. Therapeutic compounds driving uniform remodeling of tumor microenvironment (TME) across tumor types may improve the efficacy of cancer immunotherapy. ONCOS-102, a granulocyte-macrophage colony stimulating factor (GM-CSF)-expressing oncolytic adenovirus (Ad5/3-D24-GMCSF), was tested for its safety, therapeutic efficacy and capacity to remodel TME in recently completed phase I/II clinical studies in anti-PD-1 refractory melanoma (NCT03003676) and malignant pleural mesothelioma (MPM) (NCT02879669).MethodsBiopsies were obtained from tumor lesions of patients treated with intra-tumoral injections of ONCOS-102 in combination with chemotherapy or pembrolizumab for MPM and melanoma, respectively. Tumor immune infiltrates were analyzed by immunohistology using several antibody panels. On-treatment biopsies were compared to paired baseline samples as wells as to samples from control patients treated with chemotherapy alone in the case of MPM. Gene expression data obtained by next generation RNA sequencing were used to complement the immunohistology analysis and all results were correlated to clinical outcomes.ResultsComparative TME analysis of anti-PD-1 refractory melanoma and MPM tumors revealed noticeably lower baseline T-cell infiltration in mesothelioma. Thus, fractions of CD8+ T-cells were significantly below 10% in 80% of MPM biopsies while approaching or exceeding this level in 60% of melanoma baseline samples. Comparison of tumor biopsies obtained at baseline or on-treatment, demonstrated increased infiltration by both CD4+ and CD8+ T-cells in large proportions of melanoma (CD4+: 13/20 (65%); CD8+: 16/19 (84%) and MPM (CD4+: 10/15 (67%); CD8+: 9/15 (60%) tumor lesions in response to ONCOS-102. Frequencies of cytotoxic T-cells with high granzyme-B expression also increased in response to the treatment in both tumor types, in particular when assessed as percentage of total CD8+ T-cells. Other observed changes induced by ONCOS-102 in samples taken from CR, PR and SD patients with MPM or melanoma included increased CD8/Treg ratio and modulation of PD-L1 expression. Biological and clinical importance of these findings was further supported by correlation between modulation of several subsets of genes related to the process of T-cell activation, such as cytotoxic granule components and co-stimulatory molecules, and clinical response to ONCOS-102 in melanoma and both tumor response and overall survival in MPM patients.ConclusionsONCOS-102 drives pro-inflammatory modulation of immune TME across tumor types of different origins, anatomical locations and immunological baseline characteristics. Our data support potential of ONCOS-102 to serve as a potent immune sensitizing agent in combination therapies with various classes of immunomodulatory compounds and chemotherapy.

scholarly journals Distinct cellular immune profiles in the airways and blood of critically ill patients with COVID-19

2020 ◽  
Author(s):  
Anno Saris ◽  
Tom D.Y. Reijnders ◽  
Esther J. Nossent ◽  
Alex R. Schuurman ◽  
Jan Verhoeff ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Peripheral Blood ◽  
Cell Activation ◽  
Effector Memory ◽  
Activated T Cells ◽  
Immune Profile ◽  
Prolonged Icu Stay

AbstractOur understanding of the coronavirus disease-19 (COVID-19) immune response is almost exclusively derived from studies that examined blood. To gain insight in the pulmonary immune response we analysed BALF samples and paired blood samples from 17 severe COVID-19 patients. Macrophages and T cells were the most abundant cells in BALF. In the lungs, both CD4 and CD8 T cells were predominantly effector memory cells and expressed higher levels of the exhaustion marker PD-1 than in peripheral blood. Prolonged ICU stay associated with a reduced proportion of activated T cells in peripheral blood and even more so in BALF. T cell activation in blood, but not in BALF, was higher in fatal COVID-19 cases. Increased levels of inflammatory mediators were more pronounced in BALF than in plasma. In conclusion, the bronchoalveolar immune response in COVID-19 has a unique local profile that strongly differs from the immune profile in peripheral blood.SummaryThe bronchoalveolar immune response in severe COVID-19 strongly differs from the peripheral blood immune profile. Fatal COVID-19 associated with T cell activation blood, but not in BALF.

EP.WE.805From bench to bedside; A rationale for Immunotherapy in the adjuvant setting for Oesophageal cancer

2021 ◽  
Vol 108 (Supplement_7) ◽  
Author(s):  
Noel Donlon ◽  
Maria Davern ◽  
Andrew Sheppard ◽  
John Reynolds ◽  
Joanne Lysaght
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Single Agent ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Post Surgery ◽  
Post Operative Period

Abstract Background Immunotherapy is being intensively investigated for its utilisation in the curative setting as a single agent and in the multimodal setting, however, the most appropriate time to incorporate ICIs remains unknown. Our study profiles systemic anti-tumour immunity perioperatively to provide a rationale for adjuvant immunotherapy. Methods Systemic immunity was immunophenotyped pre and post-oesophagectomy on days 0, 1, 3, 7 and week 6 by flow cytometry (n = 14). The frequency of circulating lymphocytes, T cells, cytotoxic and helper T lymphocytes was profiled longitudinally including the proportion of T cell subsets in circulation. This study also profiled immune checkpoint expression on circulating T cells including: PD-1, CTLA-4, TIGIT, TIM-3, LAG-3, PD-L1 and PD-L2. Markers of immunogenicity (calreticulin, HMGB1 and MIC-A/B) were also assessed. Results The frequency of circulating CD27 + T cells increases sequentially in the immediate post-operative period peaking on day 7 in OAC patients. (p &lt; 0.01) There is a sequential decrease in the percentage of effector memory and central memory T cells in circulation and an increase in the percentage of naïve T cells in peripheral circulation of OAC patients in the immediate post-operative period. The expression of CTLA-4 on the surface of circulating CD4 + T cells decreases 6 weeks post-operatively in OAC patients. Conclusions We observed increased T cell activation and immune checkpoints immediately post-surgery with returns to baseline by week 6. These results suggest that immune checkpoint inhibitors such as anti-PD-1 may be beneficial immediately post-surgery to maintain T cell activation and prevent exhaustion of this increased population of activated T cells observed immediately post-surgery.

scholarly journals Diacylglycerol kinase ζ limits IL-2-dependent control of PD-1 expression in tumor-infiltrating T lymphocytes

2020 ◽  
Vol 8 (2) ◽  
pp. e001521
Author(s):  
Javier Arranz-Nicolás ◽  
Miguel Martin-Salgado ◽  
Cristina Rodríguez-Rodríguez ◽  
Rosa Liébana ◽  
Maria C Moreno-Ortiz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Therapeutic Potential ◽  
Interleukin 2 ◽  
Tumor Rejection ◽  
Cytotoxic T Cell ◽  
Adenocarcinoma Cells ◽  
The Impact

BackgroundThe inhibitory functions triggered by the programmed cell death-1 (PD-1) receptor following binding to its ligand (PD-L1) protect healthy organs from cytotoxic T cells, and neutralize antitumor T cell attack. Antibody-based therapies to block PD-1/PD-L1 interaction have yielded notable results, but most patients eventually develop resistance. This failure is attributed to CD8+ T cells achieving hyporesponsive states from which recovery is hardly feasible. Dysfunctional T cell phenotypes are favored by a sustained imbalance in the diacylglycerol (DAG)- and Ca2+-regulated transcriptional programs. In mice, DAG kinase ζ (DGKζ) facilitates DAG consumption, limiting T cell activation and cytotoxic T cell responses. DGKζ deficiency facilitates tumor rejection in mice without apparent adverse autoimmune effects. Despite its therapeutic potential, little is known about DGKζ function in human T cells, and no known inhibitors target this isoform.MethodsWe used a human triple parameter reporter cell line to examine the consequences of DGKζ depletion on the transcriptional restriction imposed by PD-1 ligation. We studied the effect of DGKζ deficiency on PD-1 expression dynamics, as well as the impact of DGKζ absence on the in vivo growth of MC38 adenocarcinoma cells.ResultsWe demonstrate that DGKζ depletion enhances DAG-regulated transcriptional programs, promoting interleukin-2 production and partially counteracting PD-1 inhibitory functions. DGKζ loss results in limited PD-1 expression and enhanced expansion of cytotoxic CD8+ T cell populations. This is observed even in immunosuppressive milieus, and correlates with the reduced ability of MC38 adenocarcinoma cells to form tumors in DGKζ-deficient mice.ConclusionsOur results, which define a role for DGKζ in the control of PD-1 expression, confirm DGKζ potential as a therapeutic target as well as a biomarker of CD8+ T cell dysfunctional states.

Molecular transfer of CD40 and OX40 ligands to leukemic human B cells induces expansion of autologous tumor–reactive cytotoxic T lymphocytes

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2436-2442 ◽  
Author(s):  
Ettore Biagi ◽  
Gianpietro Dotti ◽  
Eric Yvon ◽  
Edward Lee ◽  
Martin Pule ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Antibody Therapy ◽  
Interferon Γ ◽  
Lymphocytic Leukemia ◽  
Cytotoxic T Cell ◽  
Autologous Tumor ◽  
Molecular Transfer

AbstractClinical benefits from monoclonal antibody therapy for B-chronic lymphocytic leukemia (B-CLL) have increased interest in developing additional immunotherapies for the disease. CD40 ligand is an accessory signal for T-cell activation and can overcome T-cell anergy. The OX40-OX40 ligand pathway is involved in the subsequent expansion of memory antigen-specific T cells. We expressed both CD40L and OX40L on B-CLL cells by exploiting the phenomenon of molecular transfer from fibroblasts overexpressing these ligands. We analyzed the effects of the modified B-CLL cells on the number, phenotype, and cytotoxic function of autologous T cells in 7 B-CLL patients. Transfer of CD40L and OX40L was observed in all and was followed by the up-regulation of B7-1 and B7-2. The culture of CD40L/OX40L-expressing B-CLL cells with autologous T cells generated CD4+/CD8+ cytotoxic T-cell lines, which secreted interferon-γ (IFN-γ) and granzyme-B/perforin in response to autologous, but not to allogeneic, B-CLL cells or to autologous T-cell blasts. CD40L or OX40L alone was insufficient to expand tumor-reactive T cells. The combination of CD40L and OX40L on B-CLL cells may allow the generation of therapeutic immune responses to B-CLL, either by active immunization with modified tumor cells or by adoptive immunotherapy with tumor-reactive autologous T cells.

scholarly journals Transient and persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primates

Blood ◽  
2010 ◽  
Vol 116 (17) ◽  
pp. 3238-3248 ◽  
Author(s):  
Enrico Lugli ◽  
Carolyn K. Goldman ◽  
Liyanage P. Perera ◽  
Jeremy Smedley ◽  
Rhonda Pung ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
The Body ◽  
Effector Memory ◽  
Memory Cd8 T Cells

Abstract Interleukin-15 (IL-15) is a cytokine with potential therapeutic application in individuals with cancer or immunodeficiency to promote natural killer (NK)– and T-cell activation and proliferation or in vaccination protocols to generate long-lived memory T cells. Here we report that 10-50 μg/kg IL-15 administered intravenously daily for 12 days to rhesus macaques has both short- and long-lasting effects on T-cell homeostasis. Peripheral blood lymphopenia preceded a dramatic expansion of NK cells and memory CD8 T cells in the circulation, particularly a 4-fold expansion of central memory CD8 T cells and a 6-fold expansion of effector memory CD8 T cells. This expansion is a consequence of their activation in multiple tissues. A concomitant inverted CD4/CD8 T-cell ratio was observed throughout the body at day 13, a result of preferential CD8 expansion. Expanded T- and NK-cell populations declined in the blood soon after IL-15 was stopped, suggesting migration to extralymphoid sites. By day 48, homeostasis appears restored throughout the body, with the exception of the maintenance of an inverted CD4/CD8 ratio in lymph nodes. Thus, IL-15 generates a dramatic expansion of short-lived memory CD8 T cells and NK cells in immunocompetent macaques and has long-term effects on the balance of CD4+ and CD8+ T cells.

DNA vaccine with pembrolizumab to elicit antitumor responses in patients with metastatic, castration-resistant prostate cancer (mCRPC).

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 168-168 ◽  
Author(s):  
Douglas G. McNeel ◽  
Jens C. Eickhoff ◽  
Robert Jeraj ◽  
Mary Jane Staab ◽  
Jane Straus ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Dna Vaccine ◽  
T Cell Activation ◽  
Peripheral Blood ◽  
Cell Activation ◽  
Flt Pet ◽  
Pet Ct

168 Background: We have previously investigated a DNA vaccine encoding prostatic acid phosphatase (PAP, pTVG-HP) in patients with PSA-recurrent prostate cancer, and have demonstrated that this can be safely administered over many months and can elicit PAP-specific T cells. A phase 2 trial is currently underway. In preclinical models, we have found that blockade of regulatory receptors, including PD-1, at the time of T cell activation with vaccination produced anti-tumor responses in vivo. Similarly, we have recently found that patients with prostate cancer previously immunized with a DNA vaccine develop PD-1-regulated T cells. These findings suggested that combined PD-1 blockade with vaccination should elicit superior anti-tumor responses in patients with prostate cancer. Methods: A clinical trial was designed to evaluate the immunological and clinical efficacy of pTVG-HP when delivered in combination or in sequence with pembrolizumab, in patients with mCRPC. Serial biopsies, blood draws, and exploratory FLT PET/CT imaging are being conducted for correlative analyses. Results: While trial accrual continues, 1 of 14 subjects has experienced a grade 3 adverse event. There have been no grade 4 events. Several patients treated with the combination have experienced serum PSA declines, and several have experienced decreases in tumor volume by radiographic imaging at 12 weeks, including one partial response. Expansion of PAP-specific Th1-biased T cells has been detected in peripheral blood samples. Exploratory FLT PET/CT imaging has demonstrated proliferative responses in metastatic lesions and in vaccine-draining lymph nodes. Evaluation of biopsy specimens for recruitment of antigen-specific T cells is currently underway. Conclusions: PD-1 pathway inhibitors have demonstrated little clinical activity to date when used as single agents for treating prostate cancer. Our findings suggest that combining this blockade with tumor-targeted T-cell activation by a DNA vaccine is safe and can augment tumor-specific T cells, detectable within the peripheral blood and by imaging, and result in objective anti-tumor changes. Clinical trial information: NCT02499835.

scholarly journals Targeting of the Cancer-Associated Fibroblast—T-Cell Axis in Solid Malignancies

2019 ◽  
Vol 8 (11) ◽  
pp. 1989 ◽  
Author(s):  
Tom J. Harryvan ◽  
Els M. E. Verdegaal ◽  
James C. H. Hardwick ◽  
Lukas J. A. C. Hawinkels ◽  
Sjoerd H. van der Burg
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Cell Activation ◽  
Suppressor Cells ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Cell Axis ◽  
Wide Range

The introduction of a wide range of immunotherapies in clinical practice has revolutionized the treatment of cancer in the last decade. The majority of these therapeutic modalities are centered on reinvigorating a tumor-reactive cytotoxic T-cell response. While impressive clinical successes are obtained, the majority of cancer patients still fail to show a clinical response, despite the fact that their tumors express antigens that can be recognized by the immune system. This is due to a series of other cellular actors, present in or attracted towards the tumor microenvironment, including regulatory T-cells, myeloid-derived suppressor cells and cancer-associated fibroblasts (CAFs). As the main cellular constituent of the tumor-associated stroma, CAFs form a heterogeneous group of cells which can drive cancer cell invasion but can also impair the migration and activation of T-cells through direct and indirect mechanisms. This singles CAFs out as an important next target for further optimization of T-cell based immunotherapies. Here, we review the recent literature on the role of CAFs in orchestrating T-cell activation and migration within the tumor microenvironment and discuss potential avenues for targeting the interactions between fibroblasts and T-cells.

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