Randomized trial of neoadjuvant vaccination with tumor-cell lysate induces T-cell response in low-grade gliomas

Abstract BACKGROUND The prognosis of WHO grade II low-grade gliomas (LGG) is varied with potential for long survival.Given their relatively intact immune system and slow growth rate, vaccines are an attractive treatment strategy for LGG in an attempt to defer more toxic treatments. The goals of this pilot study were to evaluate safety and immunological effects of vaccination with GBM6-AD, an allogeneic glioblastoma stem cell line lysate, with poly-ICLC in LGG. METHODS Eligible patients were ≥ 18 years old, ≥ 70 KPS, with recurrent LGG or imaging consistent with LGG, and amenable to resection. Patients were randomized to vaccine prior to surgery (Arm 1) or not (Arm 2) and all received adjuvant vaccine. Co-primary outcomes were safety and immune response in the tumor, with exploratory outcomes of survival and immunologic effects in peripheral blood. RESULTS A total of 17 eligible patients were evaluable – nine into Arm 1 and eight into Arm 2. Median age was 33 years, with median time from initial diagnosis of 4.7 years (0 – 20). Two patients (11.8%) previously received radiotherapy and seven (41.2%) prior systemic therapy. No dose limiting toxicities or grade 3 AEs were observed. Neoadjuvant vaccination induced up regulation of type-1 cytokines and chemokines in peripheral blood, and CD8+ T cell clones that reacted to the vaccine were also detected in the tumor. Median follow-up time from first post-operative vaccine was 20.8 months with median PFS of 11.0 months and time to change in therapy of 23.7 months. Of the six patients to receive additional treatment, three had second surgery only one confirming malignant progression to anaplastic oligodendroglioma. CONCLUSION Treatment was well-tolerated with no regimen-limiting toxicity. GBM6-AD plus poly-ICLC induced effector CD8+ T cell response in peripheral blood and enables some vaccine-reactive CD8+ T cells to migrate into the TME. Further investigation is warranted.

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HPV-16 E7-Specific Cellular Immune Response in Women With Cervical Intraepithelial Lesion Contributes to Viral Clearance: A Cross-Sectional and Longitudinal Clinical Study

Frontiers in Immunology ◽

10.3389/fimmu.2021.768144 ◽

2022 ◽

Vol 12 ◽

Author(s):

Lina Zhang ◽

Xinyi Shi ◽

Qing Zhang ◽

Zhilei Mao ◽

Xiaoyu Shi ◽

...

Keyword(s):

T Cell ◽

Cell Response ◽

Hpv Infection ◽

T Cell Response ◽

Viral Clearance ◽

Low Grade ◽

High Grade ◽

Cross Sectional ◽

Intraepithelial Lesion ◽

Longitudinal Clinical Study

High-risk human papillomavirus (HPV) infection is the cause of almost all cervical cancers. HPV16 is one of the main risk subtypes. Although screening programs have greatly reduced the prevalence of cervical cancer in developed countries, current diagnostic tests cannot predict if mild lesions may progress into invasive lesions or not. In the current cross-sectional and longitudinal clinical study, we found that the HPV16 E7-specific T cell response in peripheral blood mononuclear cells of HPV16-infected patients is related to HPV16 clearance. It contributes to protecting the squamous interaepithelial lesion (SIL) from further malignant development. Of the HPV16 infected women enrolled (n = 131), 42 had neither intraepithelial lesion nor malignancy (NILM), 33 had low-grade SIL, 39 had high-grade SIL, and 17 had cervical cancer. Only one of 17 (5.9%) cancer patients had a positive HPV16 E7-specific T cell response, dramatically lower than the groups of precancer patients. After one year of follow-up, most women (28/33, 84.8%) with persistent HPV infection did not exhibit a HPV16 E7-specific T cell response. Furthermore, 3 malignantly progressed women, one progressed to high-grade SIL and two progressed to low-grade SIL, were negative to the HPV16 E7-specific T cell response. None of the patients with a positive HPV16 E7-specific T cell response progressed to further deterioration. Our observation suggests that HPV16 E7-specific T cell immunity is significant in viral clearance and contributes in protection against progression to malignancy.

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Low parasite specific T cell response in clinically immune individuals with low grade Plasmodium falciparum parasitaemia

Transactions of the Royal Society of Tropical Medicine and Hygiene ◽

10.1016/0035-9203(86)90295-6 ◽

1986 ◽

Vol 80 (6) ◽

pp. 1000-1001 ◽

Cited By ~ 14

Author(s):

T.G. Theander ◽

I.C. Bygbjerg ◽

L. Jacobsen ◽

S. Jepsen ◽

P.B. Larsen ◽

...

Keyword(s):

Plasmodium Falciparum ◽

T Cell ◽

Cell Response ◽

T Cell Response ◽

Low Grade

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Poorex vivoinduction of T-cell responses to idiotype or tumor cell lysate-pulsed autologous dendritic cells in advanced pre-treated multiple myeloma

Leukemia & Lymphoma ◽

10.1080/10428190500465242 ◽

2006 ◽

Vol 47 (7) ◽

pp. 1340-1347 ◽

Cited By ~ 2

Author(s):

Laurent Garderet ◽

Christelle Mazurier ◽

Catherine Pellat-Deceunynck ◽

Abdul Karim ◽

Bruno Baudin ◽

...

Keyword(s):

Multiple Myeloma ◽

Dendritic Cells ◽

T Cell ◽

Tumor Cell ◽

T Cell Responses ◽

Cell Responses ◽

Cell Lysate ◽

Tumor Cell Lysate

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Schannoma cells induce a tumor-cell-specific cytotoxic- T-cell response upon transplantation into syngeneic rats but escape elimination through the secretion of immunosuppressive factors

International Journal of Cancer ◽

10.1002/(sici)1097-0215(19970304)70:5<542::aid-ijc9>3.0.co;2-y ◽

1997 ◽

Vol 70 (5) ◽

pp. 542-550 ◽

Cited By ~ 6

Author(s):

Uwe Altenschmidt ◽

Ralf Kahl ◽

Elfriede Klundt ◽

Elisabeth Stöcklin ◽

Michael Mihatsch ◽

...

Keyword(s):

T Cell ◽

Tumor Cell ◽

Cell Response ◽

T Cell Response ◽

Cytotoxic T Cell ◽

Immunosuppressive Factors

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PKHB1 Tumor Cell Lysate Induces Antitumor Immune System Stimulation and Tumor Regression in Syngeneic Mice with Tumoral T Lymphoblasts

Journal of Oncology ◽

10.1155/2019/9852361 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

Ana Carolina Martínez-Torres ◽

Kenny Misael Calvillo-Rodríguez ◽

Ashanti Concepción Uscanga-Palomeque ◽

Luis Gómez-Morales ◽

Rodolfo Mendoza-Reveles ◽

...

Keyword(s):

Cell Death ◽

T Cell ◽

Tumor Cell ◽

Immune Tolerance ◽

Tumor Regression ◽

Ex Vivo ◽

Cell Lysate ◽

Hematological Cancers ◽

Tumor Cell Lysate

Acute lymphocytic leukemia (ALL) is the most common pediatric cancer. Currently, treatment options for patients with relapsed and refractory ALL mostly rely on immunotherapies. However, hematological cancers are commonly associated with a low immunogenicity and immune tolerance, which may contribute to leukemia relapse and the difficulties associated with the development of effective immunotherapies against this disease. We recently demonstrated that PKHB1, a TSP1-derived CD47 agonist peptide, induces immunogenic cell death (ICD) in T cell ALL (T-ALL). Cell death induced by PKHB1 on T-ALL cell lines and their homologous murine, L5178Y-R (T-murine tumor lymphoblast cell line), induced damage-associated molecular patterns (DAMPs) exposure and release. Additionally, a prophylactic vaccination with PKHB1-treated L5178Y-R cells prevented tumor establishment in vivo in all the cases. Due to the immunogenic potential of PKHB1-treated cells, in this study we assessed their ability to induce antitumor immune responses ex vivo and in vivo in an established tumor. We first confirmed the selectivity of cell death induced by PKBH1 in tumor L5178Y-R cells and observed that calreticulin exposure increased when cell death increased. Then, we found that the tumor cell lysate (TCL) obtained from PKHB1-treated L5178YR tumor cells (PKHB1-TCL) was able to induce, ex vivo, dendritic cells maturation, cytokine production, and T cell antitumor responses. Finally, our results show that in vivo, PKHB1-TCL treatment induces tumor regression in syngeneic mice transplanted with L5178Y-R cells, increasing their overall survival and protecting them from further tumor establishment after tumor rechallenge. Altogether our results highlight the immunogenicity of the cell death induced by PKHB1 activation of CD47 as a potential therapeutic tool to overcome the low immunogenicity and immune tolerance in T-ALL.

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Development and Optimization of a GMP-Compliant Manufacturing Process for a Personalized Tumor Lysate Dendritic Cell Vaccine

Vaccines ◽

10.3390/vaccines8010025 ◽

2020 ◽

Vol 8 (1) ◽

pp. 25 ◽

Cited By ~ 1

Author(s):

Caroline Boudousquié ◽

Valérie Boand ◽

Emilie Lingre ◽

Laeticia Dutoit ◽

Klara Balint ◽

...

Keyword(s):

T Cell ◽

Dendritic Cell ◽

Tumor Cell ◽

Manufacturing Process ◽

Tumor Lysate ◽

Cell Lysate ◽

Cell Factories ◽

Dc Vaccine ◽

Dc Vaccines ◽

Tumor Cell Lysate

With the emergence of immune checkpoint inhibitors and adoptive T-cell therapies, there is a considerable interest in using personalized autologous dendritic cell (DC) vaccines in combination with T cell-targeting immunotherapies to potentially maximize the therapeutic impact of DC vaccines. Here, we describe the development and optimization of a Good Manufacturing Practice (GMP)-compliant manufacturing process based on tumor lysate as a tumor antigen source for the production of an oxidized tumor cell lysate loaded DC (OC-DC) vaccine. The manufacturing process required one day for lysate preparation and six days for OC-DC vaccine production. Tumor lysate production was standardized based on an optimal tumor digestion protocol and the immunogenicity was improved through oxidation using hypochloric acid prior to freeze-thaw cycles resulting in the oxidized tumor cell lysate (OC-L). Next, monocytes were selected using the CliniMACS prodigy closed system and were placed in culture in cell factories in the presence of IL-4 and GM-CSF. Immature DCs were loaded with OC-L and matured using MPLA-IFNγ. After assessing the functionality of the OC-DC cells (IL12p70 secretion and COSTIM assay), the OC-DC vaccine was cryopreserved in multiple doses for single use. Finally, the stability of the formulated doses was tested and validated. We believe this GMP-compliant DC vaccine manufacturing process will facilitate access of patients to personalized DC vaccines, and allow for multi-center clinical trials.

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