Phase I/II Study of Marrow Infiltrating Lymphocytes (MILs) Generates Measurable Myeloma-Specific Immunity in the Autologous Stem Cell Transplant (SCT) Setting

Abstract Abstract 997 Adoptive T cell therapy requires the infusion of highly tumor specific T cells capable of trafficking to the tumor site, killing the tumor and persisting over time. MILs (as compared to peripheral blood T cells) possess many of these features (Noonan, Ca, Res. 2006). We here report the initial results from our Phase I/II trial. 22 patients were transplanted with a Melphalan-200. 19 with a CD34-selected product, 1 unselected autologous stem cells and 2 auto-BMT. 12 underwent SCT as initial consolidation and 10 patients with relapsed disease that were heavily pre-treated with an average of 3.2 prior therapies. Mean ISS score was 2.0. Average age was 56 (29–71). MILs were expanded with anti-CD3/CD28 beads for 7 days (avg. fold expansion 48.5 and avg. cell dose 2.8×10e7 CD3/kg). MILs were infused on day +3. Patients in a CR were ineligible for this study. The best clinical response included 6CRs (27%), 10PRs (45%). Autologous GVHD which was observed in 32% of patients, was limited to the skin and required no treatment. Development of this syndome did not correlate with improved clinical outcomes. Lymphoid recovery was rapid with a mean absolute lymphocyte count (ALC) on day 15 of 886 cells/ul. The laboratory immune monitoring studies were only performed in the bone marrow – the disease site and not in the peripheral blood. The percent CD3+ T cells in the BM was 13% at baseline with a CD4:CD8 ratio of 1:3. By day 60, BM T cell reconstitution was complete and showed an inversion of the CD4:8 ratio of 0.39 that persisted through day 360. At baseline, there were more CD4 effector memory (CD4EM) (CD62L−/CD45RO+) than CD4 central memory (CD4CM) (CD62L+/CD45RO+) (43% vs 27%). The CD4CM population peaked on day 60 at 43% and persisted through 1 year, CD4EM remained unchanged, and the CD4Effector decreased from 19.8% to 5.6%. The CD8 subpopulations remained unchanged from pre-SCT to 1 year post-SCT. Treg numbers doubled from harvest to post-SCT consistent with previous studies showing a greater number of Tregs in healthy BM compared to MM-BM. Activated T cells (CD69+) doubled from pre- to post-SCT. IFNγ production in both CD4 and CD8 cells more than doubled compared to pre-SCT and was maintained at 1 year suggesting the persistence of the infused MILs. The immune monitoring in the BM based on clinical responses revealed that patients achieving a CR/PR showed greater CD8 numbers at day +60 compared to stable disease (SD) or progressive disease (PD)(14.5% vs. 7.6%, respectively) and inversion of the CD4/CD8 ratio at 1 year (0.55 vs 1.26). In patients with SD or PD, the immune infiltrate in the BM was characterized by a large numbers of effector and effector-memory T cells and few CD8CM at baseline. CR patients possessed the fewest CD8Effector and the most CD8CM with persistence of CD8CM out to one year. These patients also showed a greater expansion in IFNγ cells as well as a greater amount of IFNγ production at each time point. Importantly, tumor-specific IFNγ production of CD3 cells in the BM was predictive of a clinical response. Patients achieving a CR showed twice the antigen-specific IFNγ production compared to all other groups at day 180 which persisted through 1 year. Analyses of additional immune subsets will be discussed in greater detail. This is the first reported trial utilizing activated MILs as a source of tumor specific T cells. We have demonstrated the ability to effectively expand MILs ex vivo and provide an analysis of the parameters of immune reconstitution demonstrating that the clinical outcome correlated with the robustness of the immune response in the BM. Disclosures: Luznik: Otsuka Pharmaceuticals: Research Funding.

Download Full-text

Role of Adoptive T- Cell Therapy in Post Hematopoietic Stem Cells Transplant Viral Infections-: A Systemic Review

Blood ◽

10.1182/blood-2020-139284 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 14-16

Author(s):

Hassaan Imtiaz ◽

Muhammad Saad Farooqi ◽

Unaiza Faizan ◽

Saad Ur Rehman ◽

Muhammed Hamza Arshad ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

Phase I ◽

Viral Infections ◽

Adoptive T Cell Therapy ◽

Control Group ◽

T Cell Therapy ◽

And Control ◽

Cmv Reactivation

Introduction Allogenic hematopoietic stem cell transplantation (Allo-HSCT) used for the treatment of multiple hematological malignancies requires immunosuppression, that can lead to the reactivation of viruses like EBV, CMV, adenovirus (AdV). These viruses pose a life-threatening risk to an individual like Graft vs Host Disease (GVHD) and other virus-specific complications. Adoptive T cell therapy (ATC) is an approach to treat refractory post-Allo-HSCT transplant viral infections. The aim of this study is to assess the efficacy of various ATCs being developed against various viruses. Methods A systematic search on PubMed, Embase, Clinicaltrials.gov, and Web of Science was performed for adoptive immunotherapy in viral infections after stem cell transplantation from inception to May 28, 2020. Out of 604 studies, 13 phase I and II clinical trials were selected for the systematic review. Results A total of 13 studies were included of which two studies included data on the pediatric population (n=13). A total of 335 patients (pts) were enrolled in 13 studies of which 264 were evaluable. CMV Perruccio et al. (2005) in a randomized controlled trial (RCT) assessed the efficacy of ATC against both Aspergillus and CMV after alloSCT. Median follow up (f/u) was six months. For Aspergillus (n=23), 90% and 54% achieved clearance, while for CMV (n=68) 92% and 9% didn't develop CMV reactivation in treatment and control group respectively. Overall Survival (OS) and progression-free survival (PFS) rate at two years were 92% and 80% respectively. Smith et al. (2018) (n=21) in a phase I trial studied the transfusion of virus-specific T cells (VST) (n=13) against CMV infection after undergoing alloSCT. After a median f/u of 28 weeks, overall response rate (ORR) was 85%. Bao et al. (2012) (n=10) conducted a study with VST transfusion against CMV infection (n=7). ORR was 85% of which 3 pts who were on immunosuppressive had shown reactivation. Miej et al. (2012) in phase I/II study (n=6) assessed the response of VST against refractory CMV with CR of 100% Neuenhahn et al. (2017) studied a phase I/II prospective trial (n=17) (CMV Seropositive graft donor (D+) 9/17 and CMV Seronegative graft donor (D-) 8/17) with CR of 62% in D+ group. In D- group only 37% developed T cells after Third-Party Donor transfer and only these achieved CR, while pts with no T cell detection in D- group (63%), only one achieved CR. Micklethwaite et al. (2008) did a phase I clinical trial (n=12) of CMV specific T cells given prophylactically. Only four pts showed CMV reactivation. Adenovirus Feucht et al. (2019) performed a phase I/II clinical trial (n=30) of VST against refractory AdV infection. 47% showed CR, 13% with negative blood AdV cleared virus from other sites, 10% showed PR. OS at six months was 71%. Winnie et al. (2018) (n=8) conducted phase I/II RCT among pediatric pts. Median f/u was six months. All patients have shown a decrease in AdV viral load. Qasim et al. (2013) conducted a prospective trial (n=5) among pediatric pts with CR of 60% until six weeks f/u. 20% died due to AdV viremia. Multi-virus CTLs Gerdemann et al. (2013) (n=36) did a clinical trial by infusing multi-virus cytotoxic T lymphocytes (CTLs) (n=10), reactive against CMV, EBV, and AdV. CR in 80% of the pts. Muranski et al. (2017) performed a phase I trial (n=9) and infused multi-virus CTLs prophylactically. No AdV, BK, or EBV related disease was observed in any pts while 11% pts had asymptomatic AdV viremia. Only those pts who received steroid therapy had CMV reactivation (44%). Ma et al. (2015) performed a phase I/II RCT with an intervention group (n=19, evaluable=10) and control group (n=33) with an infusion of multi-virus CTLs against CMV, EBV, AdV, and VZV after alloSCT, prophylactically. Pts in the intervention group had no reactivation of EBV, AdV, or VZV. 6 (60%) pts with CMV had reactivation; four before T cell therapy and two in the context of steroid therapy. OS at one year was 89% and 81% in the intervention and control group respectively. Third-Party Donor T-cells Tzannou et al. (2017) (n=37) in a phase II study demonstrated ORR of 92% (95% CI, 78.1% to 98.3%) in various viruses with ORR for BK virus 100%, CMV 94%, Adv 71%, EBV 100% and HHV-6 67%. Conclusion Adoptive T cell therapy for viral infections has shown efficacy in Post- allo-SCT pts who achieved complete clearance of infection in many cases, showed only minimal adverse events, and no major risk for GVHD related to this therapy was noted. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Download Full-text

Adoptive T-cell therapy (ACT) with TILs for metastatic melanoma: Clinical responses and durable persistence of anticancer responses in peripheral blood.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.3028 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 3028-3028 ◽

Cited By ~ 2

Author(s):

Marco Donia ◽

Rikke Andersen ◽

Eva Ellebaek ◽

Trine Zeeberg Iversen ◽

Mads Hald Andersen ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Metastatic Melanoma ◽

Peripheral Blood ◽

Intracellular Cytokine Staining ◽

Adoptive T Cell Therapy ◽

Medium Size ◽

T Cell Therapy ◽

Hematopoietic Stem ◽

Clinical Responses

3028 Background: TIL treatment holds the promise to introduce a new treatment paradigm into oncology practice. To demonstrate the logistical feasibility of this complex approach in Europe, at Herlev Hospital, Denmark, we have initiated a trial for patients with metastatic melanoma and evaluated the melanoma-specific immunity in the peripheral blood. Methods: We present the updated results of trial NCT00937625. The study takes place in a medium-size academic center (30 in-patient oncology beds) equipped with a 36 square meters cGMP cell production lab integrated in a hematopoietic stem cell transplantation unit. Patients were treated with autologous TILs preceded by standard lymphodepleting chemotherapy but followed by attenuated regimens of IL-2 (n=6 low-dose s.c. for 14 days; n=9 i.v. intermediate decrescendo dose). Melanoma-specific responses were assessed with intracellular cytokine staining. Results: We have generated TILs from 28/31 patients, with 15 patients treated so far and many TILs cryopreserved for future use. Patients were treated with an average of >50x109 CD4+, CD8+and a small but consistent fraction of γδ TILs. The lower doses of IL-2 have significantly decreased the classical toxicity of the treatment associated with more harsh IL-2 regimens, and response evaluation showed the achievement of three CR lasting > 1 year and four PR. Clinical responses were associated with high numbers of tumour reactive T-cells infused. Importantly, in most responding patients we observed induction and durable persistence (up to 1 year) of anti-melanoma T-cell responses in the peripheral blood. Conclusions: A high response rate including durable complete responses can be induced after treatment with TILs followed by an attenuated regimen of IL-2, which significantly reduced the occurrence of severe side effects. Effective TIL treatment is associated with induction and long-term persistence in the blood of T cells producing in vitro anticancer responses. By showing that TIL-based ACT is logistically feasible and accessible to medium-size academic centers, we open the possibility for testing this treatment in a large randomized setting in Europe. Clinical trial information: NCT00937625.

Download Full-text

Engraftment of human central memory-derived effector CD8+ T cells in immunodeficient mice

Blood ◽

10.1182/blood-2010-10-310599 ◽

2011 ◽

Vol 117 (6) ◽

pp. 1888-1898 ◽

Cited By ~ 115

Author(s):

Xiuli Wang ◽

Carolina Berger ◽

ChingLam W. Wong ◽

Stephen J. Forman ◽

Stanley R. Riddell ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Effector T Cells ◽

Central Memory ◽

Model Systems ◽

Adoptive T Cell Therapy ◽

Effector Memory ◽

T Cell Therapy ◽

Effector Cells

Abstract In clinical trials of adoptive T-cell therapy, the persistence of transferred cells correlates with therapeutic efficacy. However, properties of human T cells that enable their persistence in vivo are poorly understood, and model systems that enable investigation of the fate of human effector T cells (TE) have not been described. Here, we analyzed the engraftment of adoptively transferred human cytomegalovirus pp65-specific CD8+ TE cells derived from purified CD45RO+CD62L+ central memory (TCM) or CD45RO+CD62L− effector memory (TEM) precursors in an immunodeficient mouse model. The engraftment of TCM-derived effector cells (TCM/E) was dependent on human interleukin-15, and superior in magnitude and duration to TEM-derived effector cells (TEM/E). T-cell receptor Vβ analysis of persisting cells demonstrated that CD8+ TCM/E engraftment was polyclonal, suggesting that the ability to engraft is a general feature of TCM/E. CD8+ TEM/E proliferated extensively after transfer but underwent rapid apoptosis. In contrast, TCM/E were less prone to apoptosis and established a persistent reservoir of functional T cells in vivo characterized by higher CD28 expression. These studies predict that human CD8+ effector T cells derived from TCM precursors may be preferred for adoptive therapy based on superior engraftment fitness.

Download Full-text

CTIM-07. IDENTIFICATION OF A BASELINE BIOMARKER ASSOCIATED WITH TUMOR RESPONSES IN A PHASE I/IIa TRIAL OF A THERAPEUTIC CMV VACCINE AGAINST RECURRENT GLIOBLASTOMA (GBM)

Neuro-Oncology ◽

10.1093/neuonc/noaa215.141 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii34-ii34

Author(s):

Patrick Wen ◽

David Reardon ◽

Deborah Forst ◽

Eudocia Lee ◽

Fabio Iwamoto ◽

...

Keyword(s):

T Cells ◽

Phase I ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Brain Mri ◽

Absolute Lymphocyte Count ◽

Immune Monitoring ◽

Recurrent Glioblastoma ◽

Effector Memory ◽

Intradermal Vaccination

Abstract Cytomegalovirus (CMV) antigens have been reported in over 90% of GBM tumors. CD4+ and CD8+ T cells are most frequently directed against the gB and pp65 antigens, respectively, and are immunogenic targets in a CMV-based GBM vaccine. We enrolled 10 patients (6 women, 4 men) with KPS at least 70 and first recurrence of GBM to a trial (Phase IIa extension) of gB/pp65 enveloped virus-like particles (eVLPs) with GM-CSF. Intradermal vaccination was administered every 4 weeks, with serologic immune-monitoring 2 weeks after each vaccination and surveillance brain MRI scans every 6 weeks. Median age was 59 years (range 33–67). Among 8 response-evaluable patients, we observed 1 SD and 1 PR. Among all patients treated on phase I and II (n=26), a normal baseline ratio of CD4/CD8 T cells in peripheral blood predicted response (n=6). Other baseline peripheral blood markers did not correlate with efficacy, including total white blood cell, lymphocyte percentage, and absolute lymphocyte count. During treatment, the peripheral blood of responders demonstrated dynamic losses followed by subsequent reappearance and expansion of CMV-specific CD4+ effector memory T cells. Based on these encouraging results, a new arm is enrolling subjects combining gB/pp65 eVLPs (at the same dose) formulated with adjuvant intramuscular AS01B and results will be presented.

Download Full-text

Impact of the Conditioning Chemotherapy On Outcomes in Adoptive T Cell Therapy: Results From a Phase I Clinical Trial of Autologous CD19-Targeted T Cells for Patients with Relapsed CLL

Blood ◽

10.1182/blood.v120.21.1797.1797 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1797-1797 ◽

Cited By ~ 4

Author(s):

Jae H. Park ◽

Isabelle Rivière ◽

Xiuyan Wang ◽

Jolanta Stefanski ◽

Qing He ◽

...

Keyword(s):

Clinical Trial ◽

T Cells ◽

T Cell ◽

Cell Therapy ◽

Phase I ◽

B Cell ◽

Tumor Burden ◽

Adoptive T Cell Therapy ◽

T Cell Therapy ◽

Conditioning Therapy

Abstract Abstract 1797 Patient T cells may be genetically modified to express chimeric antigen receptors (CARs) targeted to antigens expressed on tumor cells. We have previously reported initial results from a phase I clinical trial treating patients with chemotherapy refractory chronic lymphocytic leukemia (CLL) with autologous T cells modified to express the 19–28z CAR targeted to the CD19 antigen expressed on most B cell malignancies (Brentjens RJ, Rivière I et al., Blood, 2011;118(18):4817-28). In the previous reported cohorts of 8 patients, CAR-modified T cells were infused in the setting of rapidly progressive and chemotherapy refractory disease. Although prior conditioning therapy with cyclophosphamide enhanced in vivo persistence of the modified T cells, all patients had cyclophosphamide-resistant disease and none experienced objective remissions or significant hematologic recovery. We hypothesized that suboptimal clinical response observed in the study was because of a large tumor burden at the time of T cell infusion and refractoriness to conditioning therapy. On the basis of these findings, we have modified the protocol to allow prior cytoreductive therapy and conditioning with chemotherapeutic agents based on predicted chemosensitivity. Since these protocol modifications, two patients have been treated. Both had relapsed disease with unfavorable disease phenotype following previous treatments with various chemotherapy and biologic regimens. Of the two patients treated to date, one achieved partial remission (PR) and the other attained minimal residual disease (MRD)-negative complete remission (CR) according to standard international criteria. The first patient experienced reduction in peripheral lymphocytosis and obtained stable disease with persistent anemia and thrombocytopenia after two cycles of bendamustine and rituximab (BR). Following the bendamustine conditioning and modified T cell infusion, PR was achieved with complete hematologic recovery, lasting for more than 8 months at the time of this report. The second patient achieved PR following two cycles of BR and subsequently attained MRD-negative CR with concomitant development of B cell aplasia after receiving the bendamustine conditioning and CAR-modified T cells. At the time of this report, the response has been sustained for more than 5 months. Notably, this patient has long-term persistence of the CAR-modified T cells, detected at 12 weeks following the T cell infusion. No significant toxicities were observed in the two patients, except for fevers lasting 3–4 days and transient grade 2 hypoxia. While the number of treated patients on the revised protocol is too small to draw a definitive conclusion, our findings of a significant improvement in the degree and depth of response with the bendamustine conditioning compared to our previous cohorts of cyclophosphamide-refractory CLL who received cyclophosphamide as their conditioning suggest a potentially greater effect of conditioning regimens through tumor burden reduction than the induction of a supportive cytokine response or lymphocyte depletion. In light of these initial observations, the role of the conditioning chemotherapy regimen given prior to adoptive T cell therapy needs to be carefully evaluated since not all regimens may ultimately be equally effective with respect to clinical outcomes. Disclosures: Lamanna: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

PD-1 Expression Is Markedly Upregulated on Intratumoral CD4+ and CD8+ T Cells in Follicular Lymphoma and Is Associated with T-Cell Exhaustion.

Blood ◽

10.1182/blood.v110.11.2749.2749 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2749-2749 ◽

Cited By ~ 1

Author(s):

Durgha Nattamai ◽

Sattva S. Neelapu

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

Follicular Lymphoma ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Cell Function ◽

Adoptive T Cell Therapy ◽

T Cell Therapy ◽

T Cell Function

Abstract Follicular lymphoma is one of the most immune-responsive of all human malignancies. However, immunoregulatory mechanisms in the tumor microenvironment may impair the efficacy of immunotherapies such as vaccines and adoptive T-cell therapy. The inhibitory receptor programmed death 1 (PD1), a negative regulator of activated T cells was recently shown to be upregulated on the surface of HIV-specific CD4+ and CD8+ T cells in humans and was associated with impaired T-cell function. Blockade of the immunoregulatory PD-1/PD-ligand 1 (PD-L1) pathway with antibodies against the PD-L1 augmented the function of HIV-specific CD4+ and CD8+ T cells (Day CL et al, Nature, 2006). To investigate the role of PD-1 in lymphoma, we examined PD-1 expression on peripheral blood mononuclear cells (PBMC) and intratumoral T cells in patients with follicular lymphoma prior to therapy. We observed that PD-1 expression is significantly upregulated on peripheral blood and intratumoral CD4+ and CD8+ T cells in patients with follicular lymphoma as compared with normal donor PBMC. Furthermore, PD-1 expression was significantly higher on intratumoral (mean 61%, range 34% to 86%) compared with peripheral blood CD4+ T cells (mean 25%, range 9 to 40%). Likewise, PD-1 expression was significantly higher on intratumoral (mean 44%, range 31% to 69%) compared with peripheral blood CD8+ T cells (mean 16%, range 9 to 31%). PD-1 expression on CD4+ and CD8+ T cells was associated with impaired type 1 cytokine production (IL-2, TNFa, and IFNg) and blockade of the PD-1/PD-ligand pathway with antibodies against PD-1 significantly enhanced T-cell function. These data indicate that the immunoregulatory PD-1/PD-ligand pathway is operative in patients with follicular lymphoma. Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T-cells in follicular lymphoma in combination with other immunomodulatory strategies such as vaccines and adoptive T-cell therapy.

Download Full-text

Clinical Grade Generation of T-Helper-1-Driven Polyclonal T-Cell Populations for Adoptive Immunotherapy Against Tumor Associated Antigens

Blood ◽

10.1182/blood.v118.21.4314.4314 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4314-4314

Author(s):

Simone Kayser ◽

Cristina Boß ◽

Vanya Icheva ◽

Stefan Stevanovic ◽

Peter Lang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

Peripheral Blood ◽

Adoptive T Cell Therapy ◽

T Helper ◽

T Cell Therapy ◽

Tumor Associated Antigens ◽

Healthy Donors ◽

Ifn Γ

Abstract Abstract 4314 Adoptive T cell therapy has been shown an option to treat patients with malignancies. In contrast to vaccinations, T cells for adoptive T-cell therapy are generated ex vivo to be re-infused into the recipient. This enables treatment of immunocompromized hosts and use of allogeneic T cells to exploit graft versus tumor effects. Adoptive T-cell therapy involving CD4+ T-helper cells (Th cells), intends to induce sustained T-cell responses in vivo. The Th1 cytokine interferon-gamma (IFN-γ) has not only an effect in orchestrating cytotoxic T-cell reponses, IFN-γ by itself has antitumor effects. Transferring T cells in a lymphopenic host furthermore eliminates regulatory T cells (Tregs) and offers access to homeostatic cytokines. The aim of our study was the translation of preclinical data into a GMP conform clinical scale protocol to generate specific T cells for adoptive T-cell therapy against tumor associated antigens. Large scale generations of NY-ESO-1 specific T cells was performed according to current GMP regulations in a GMP facility. In brief, peripheral blood mononuclear cells from healthy donors were primed with an overlapping NY-ESO-1 15-mer peptide mix. The priming was done in the presence of IL-7 and IL-2. T cells were enriched using IFN-γ capture technique and expanded for two weeks in autologous culture conditions with IL-7, IL-15 and IL-2. T-cell specificity, function and proliferation capacity was analyzed by flow cytometry. The T-cell products showed high numbers of specifically IFN-γ+, TNF-alpha+ T cells. Tolerance inducing cytokines like IL-10 were absent. Enrichment of Tregs was excluded. Both, CD4+ and CD8+ T cells with an effector memory phenotype proliferated in response to NY-ESO-1. CD107a assays demonstrated cytotoxic capacities of T cells. The T-cell product did not include alloreactive T cells. In summary GMP-conform generation of NY-ESO-1 specific T cells was established. Although tumor associated antigens are potential self antigens, it is possible to induce a functional Th1 response in peripheral blood T cells from healthy donors. Adoptive T-cell therapy against tumor associated antigens could have implications for multiple tumor entities in autologous as well as allogeneic treatment approaches. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

A modular and controllable T cell therapy platform for acute myeloid leukemia

Leukemia ◽

10.1038/s41375-020-01109-w ◽

2021 ◽

Author(s):

Mohamed-Reda Benmebarek ◽

Bruno L. Cadilha ◽

Monika Herrmann ◽

Stefanie Lesch ◽

Saskia Schmitt ◽

...

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

T Cell ◽

Cell Therapy ◽

Myeloid Leukemia ◽

Tumor Antigens ◽

Adoptive T Cell Therapy ◽

Single Chain ◽

T Cell Therapy ◽

Acute Myeloid

AbstractTargeted T cell therapy is highly effective in disease settings where tumor antigens are uniformly expressed on malignant cells and where off-tumor on-target-associated toxicity is manageable. Although acute myeloid leukemia (AML) has in principle been shown to be a T cell-sensitive disease by the graft-versus-leukemia activity of allogeneic stem cell transplantation, T cell therapy has so far failed in this setting. This is largely due to the lack of target structures both sufficiently selective and uniformly expressed on AML, causing unacceptable myeloid cell toxicity. To address this, we developed a modular and controllable MHC-unrestricted adoptive T cell therapy platform tailored to AML. This platform combines synthetic agonistic receptor (SAR) -transduced T cells with AML-targeting tandem single chain variable fragment (scFv) constructs. Construct exchange allows SAR T cells to be redirected toward alternative targets, a process enabled by the short half-life and controllability of these antibody fragments. Combining SAR-transduced T cells with the scFv constructs resulted in selective killing of CD33+ and CD123+ AML cell lines, as well as of patient-derived AML blasts. Durable responses and persistence of SAR-transduced T cells could also be demonstrated in AML xenograft models. Together these results warrant further translation of this novel platform for AML treatment.

Download Full-text

IMMU-31. QUANTITATIVE EVALUATION OF ROUTES OF ADMINISTRATION OF IMMUNOTHERAPEUTIC T CELLS TO ORTHOTOPIC GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa215.461 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii111-ii111

Author(s):

Lan Hoang-Minh ◽

Angelie Rivera-Rodriguez ◽

Fernanda Pohl-Guimarães ◽

Seth Currlin ◽

Christina Von Roemeling ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Tumor Growth ◽

Ex Vivo ◽

Adoptive T Cell Therapy ◽

Whole Body ◽

T Cell Therapy ◽

Clinical Responses

Abstract SIGNIFICANCE Adoptive T cell therapy (ACT) has emerged as the most effective treatment against advanced malignant melanoma, eliciting remarkable objective clinical responses in up to 75% of patients with refractory metastatic disease, including within the central nervous system. Immunologic surrogate endpoints correlating with treatment outcome have been identified in these patients, with clinical responses being dependent on the migration of transferred T cells to sites of tumor growth. OBJECTIVE We investigated the biodistribution of intravenously or intraventricularly administered T cells in a murine model of glioblastoma at whole body, organ, and cellular levels. METHODS gp100-specific T cells were isolated from the spleens of pmel DsRed transgenic C57BL/6 mice and injected intravenously or intraventricularly, after in vitro expansion and activation, in murine KR158B-Luc-gp100 glioma-bearing mice. To determine transferred T cell spatial distribution, the brain, lymph nodes, heart, lungs, spleen, liver, and kidneys of mice were processed for 3D imaging using light-sheet and multiphoton imaging. ACT T cell quantification in various organs was performed ex vivo using flow cytometry, 2D optical imaging (IVIS), and magnetic particle imaging (MPI) after ferucarbotran nanoparticle transfection of T cells. T cell biodistribution was also assessed in vivo using MPI. RESULTS Following T cell intravenous injection, the spleen, liver, and lungs accounted for more than 90% of transferred T cells; the proportion of DsRed T cells in the brains was found to be very low, hovering below 1%. In contrast, most ACT T cells persisted in the tumor-bearing brains following intraventricular injections. ACT T cells mostly concentrated at the periphery of tumor masses and in proximity to blood vessels. CONCLUSIONS The success of ACT immunotherapy for brain tumors requires optimization of delivery route, dosing regimen, and enhancement of tumor-specific lymphocyte trafficking and effector functions to achieve maximal penetration and persistence at sites of invasive tumor growth.

Download Full-text