Administration of Granulocyte-macrophage colony-stimulating factor enhanced CAR T-cell expansion and cellular immunity recovery without inducing cytokine release syndrome: a retrospective study

doi:10.21203/rs.3.rs-1673301/v1

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Administration of Granulocyte-macrophage colony-stimulating factor enhanced CAR T-cell expansion and cellular immunity recovery without inducing cytokine release syndrome: a retrospective study

https://doi.org/10.21203/rs.3.rs-1673301/v1

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Background: Leukopenia and cytokine release syndrome (CRS) are two major toxicities of CAR-T cell therapy. GM-CSF is an ideal candidate treatment for leukopenia except for its potential aggravation of CRS. We hypothesized that the optimal timing of supplemental with GM-CSF in a shortage of host immunity and CAR T-cell was chosen as avoidance of CRS. In the study we evaluated the safety and efficacy of GM-CSF intervention post-CAR T-cell therapy while circulating CAR T-cell declined.

Methods: Nine patients received GM-CSF therapy who displayed moderate leukopenia with white blood cell counts (WBC) <3000 cells/mm³ and absolute neutrophil counts (ANC) <1500 cells/mm³ with concomitant declination of circulating CAR T-cell after CAR T-cell therapy.

Results: The median duration of GM-CSF intervention was 15 days (4-30). CAR T-cell expansion was observed in eight patients (8/9), including cerebrospinal fluid of one patient and peripheral blood (PB) of other seven patients. And the peaks of CAR T-cell levels in cerebrospinal fluid and PB appeared in day 6 and day 7 (2-11) following the initiation of GM-CSF administration. Also, increased white blood cells in PB was observed in all patients. The median onset and duration time of WBC recovery were 9 (1-14) and 17(3-53) days. Moreover, the increment of WBC, neutrophil, lymphocyte and CD3-CD16+CD56+ natural killer cell in PB was observed. In addition, no CRS or fatal infection occurred during GM-CSF treatment.

Conclusion: This study provides evidence for the clinical feasibility of combining CAR T-cell therapy with the GM-CSF to treat leukopenia patients with concomitant declination of circulating CAR T-cell.

Chimeric antigen receptor T-cell

Granulocyte-macrophage colony-stimulating factor

leukopenia

cytokine release syndrome

Chimeric antigen receptor T-cell (CAR T) therapy has been shown to be a promising remedy in varieties of hematological cancers [1–4]. However, the efficacy of CAR T-cell therapy is limited by lack of persistence of CAR T cells and side effects associated with CAR T-cell infusion, including leukopenia, infection and cytokine release syndrome (CRS). Therefore, the overall management of CAR T-cell persistence, leukopenia recovery, as well as CRS intervention is urgently needed to enhance the long-term remission, prevent the life-threatening infection, as well as to alleviate the CRS and neurotoxicity associated with CAR T-cell therapy [5].

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an important hematopoietic growth factor and immune modulator[6]. Although GM-CSF is produced locally, it can act in a paracrine fashion to recruit circulating neutrophils, monocytes and lymphocytes to enhance their functions in host defense [6]. GM-CSF has been widely used in clinics for the treatment of severe leukopenia for patients receiving chemotherapy. In the previous clinical trial, we have demonstrated administration of GM-CSF is an effective strategy not only in immune modulation, but also in reduction of fungal infections due to neutropenia following pre-hematopoietic stem cell transplantation (HSCT) conditioning [7]. However, to our knowledge, no clinical study has been reported in the beneficial effects of GM-CSF administration in patients undergone CAR T-cell treatment while circulating CAR T-cell declined.

Here we explored GM-CSF as a therapeutic intervention aimed at alleviating leukopenia, promoting cellular immunity recovery, as well as enhancing CAR T-cell expansion in patients. In this cohort, nine patients undergone different CAR T-cell therapies have been treated with GM-CSF, to assess the safety and efficacy of GM-CSF intervention post-CAR T-cell therapy.

Patient characteristics and study design

This retrospective study was designed to examine the safety and efficacy of GM-CSF in treatment of leukopenia post-CAR T-cell therapy at Shanghai Zhaxin Traditional Chinese and Western Medicine Hospital. The protocol for CAR T-cell therapies has been approved by the Hospital ethics committee. Nine patients undergone CAR T-cell treatments, who suffered from leukopenia with concomitant declination of circulating CAR T-cell were enrolled. The patients have received various CAR T-cell therapies targeting CD7, CD19, CD20 and CD22 cell surface receptors. The CAR T-cell manufacture and detection were performed as previously reported [2, 3]. The criteria for assessment of therapeutic effects for acute lymphoblastic leukemia and lymphoma were defined in accordance with NCCN guidelines version 4.2021 (Acute Lymphoblastic Leukemia) and Lugano 2014. After CAR T-cell infusion, clinical outcomes including overall survival (OS) and relapse were evaluated up to date as of May 12 2022. The severities of cytokine releasing syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were also assessed by NCCN guidelines version 4.2021 (Management of CAR T-cell-Related Toxicities).

Gm-csf Treatment

Patients undergone CAR T-cell therapy have been treated with GM-CSF when they developed leukopenia with concomitant declination of circulating CAR T-cell. GM-CSF was subcutaneous administrated. The indication for initiation of GM-CSF therapy was patients who display moderate leukopenia with white blood cell counts (WBC) < 3000 cells/mm³ and absolute neutrophil counts (ANC) < 1500 cells/mm³. The indication for termination of GM-CSF therapy, was either when their WBC and ANC levels had reached to 5000–10000 cells/mm³ and 3000–5000 cells/mm³, respectively. All patients started GM-CSF at 100ug daily. After 3 days, the dose of GM-CSF in two patients was escalated to 200ug daily because no increment in WBC and neutrophils was observed. The primary objective of this study was to assess the safety of GM-CSF administration and the secondary objective was to evaluate the efficacy of GM-CSF intervention post-CAR T-cell therapy in alleviating leukopenia and enhancing the persistence of CAR T-cell.

Statistical analysis

Statistical analysis was performed with SPSS software and Data Analysis version 23.0. Difference of continuous variables between different weeks was analyzed by paired two-tailed Student's t test (cytokines and cell count). The Kaplan-Meier approach was performed to estimate overall survival. Data is considered to be statistically significant when P < 0.05.

CAR T-cell expansion post-GM-CSF administration

Nine patients were enrolled in cohort from May 2021 and November 2021 to receive GM-CSF therapy at Shanghai Zhaxin Traditional Chinese and Western Medicine Hospital whose clinical characteristics are shown in Table 1. The median duration of GM-CSF intervention was 15 days (4–30). The median interval between start of GM-CSF and CAR T-cell infusion was 20 days (8-126).

We serially evaluated CAR T-cell expansion in patients with GM-CSF. Seven out of nine patients (77.8%) experienced CAR T-cell expansion in peripheral blood (PB) during GM-CSF usage (Fig. 1A). The median baseline and peak CAR T cells count in PB of the seven patients with CAR T-cell expansion were 0.85×10⁶/L (0-50.9) and 6.06×10⁶/L (1.43-112.55). The peaks of CAR T-cell levels appeared in day 7(2–11) following the initiation of GM-CSF administration. In addition, although no increased CAR T-cell count in PB was observed in patients #8 and #9, the percentage of CAR T-cell in cerebrospinal fluid of patient #8 increased from 4.43–35.78% at day 6 and dropped to 1.38% at day 10 meanwhile GM-CSF was administrated (Fig. 1B).

The Increment Of White Blood Cells After Initial Gm-csf Administration

We found increased white blood cells in PB of all patients with GM-CSF. The median time to achieve a WBC level above 3000 cells/mm³ was 9 (1–14) days following the initiation of GM-CSF administration. Then there was only one patient (#2) whose WBC count never dropped below 3000 cells/mm³ again. In the other eight patients(88.89%), the median duration of WBC recovery was 17(3–53) days and then WBC count dropped below 3000 cells/mm³.

White blood cell count in PB of all patients gradually increased every week after GM-CSF administration. White blood cell count in PB prior to GM-CSF administration was 2.194×10⁹/L improved to 3.839×10⁹/L at the second week (P = 0.032, paired t-test), to 4.398×10⁹/L at the third week (P = 0.024, paired t-test) and to 4.965×10⁹/L at the fourth week (P = 0.025, paired t-test). Also, the increment of neutrophil, lymphocyte and CD3-CD16 + CD56 + natural killer cell was observed in PB. The mean of neutrophil count in PB every week before and after GM-CSF initiated were 1.066×10⁹/L, 2.134×10⁹/L, 2.239×10⁹/L, 2.564×10⁹/L and 2.488×10⁹/L. There was statistically significant difference in neutrophil count between baseline and the third week (P = 0.037, paired t-test). Moreover, lymphocyte in PB was significantly increased at the third (P = 0.025, paired t-test) and fourth (P = 0.024, paired t-test) weeks compared to at the first week after GM-CSF administration. In addition, paired t-test statistical analysis revealed a significant increase in CD3-CD16 + CD56 + natural killer cell count between the first and third weeks (56.09×10⁶/L vs 83.41×10⁶/L, P = 0.006, paired t-test). However, there were no significant difference observed in monocyte and CD3 + cell count at the baseline and 4-week follow-up (Fig. 2).

The Administration Of Gm-csf Alleviated Inflammation Indicators In Patients

Inflammatory markers, such as cytokines, C-reactive protein (CRP) and ferritin, were monitored in this study. However, no significant increment of inflammatory markers was observed. On the contrary, the statistically significant decreases in the mean of cytokines (IL-17F, IL-1β, IL-4, TNF-α and TNF-β) and C-reactive protein (CRP) were seen at the 4-week follow-up (P > 0.05) (Figs. 3 and 4). Furthermore, we also found the serum GM-CSF level in PB of patient 7 which remained within the normal range at the 2-week follow-up (7.7, 11 and 11.8, normal range 0-39pg/ml).

Clinical Description Of Patients

A total of nine patients with ALL and NHL in the cohort, median age 39 (20–59) years old, were treated at Shanghai Zhaxin Traditional Chinese and Western Medicine Hospital. The detailed characteristics of all patients are shown in Table 1. Four patients had ALL and NHL in first to three relapse, five patients had primary refractory disease. One patient (#4) had relapsed after prior allogeneic hematopoietic stem cell transplant (allo-HSCT). Three patients (#3, 7 and 8) had undergone autologous HSCT (auto-HSCT). Three patients (#3, 7 and 9) had previously been treated with CAR T-cell. The previous times of treatments were 435 (136–1613) days. Autologous CAR T-cell were infused in 8 patients without prior allo-HSCT, while donor-derived CAR T-cell were infused in 1 post-allo-HSCT patient (#4). The median dose for CAR T-cell infusion was 1.2 (0.63–2.79) ×10⁶ cells per kilogram of body weight.

At a median observation time of 238 (70–346) days, two patients (#1 and #9) were bridged to allo-HSCT and patient No.5 was bridged to auto-HSCT. Two patients (#1 and #4) died of infection at day 184 and 155. Cancer-related death occurred in patient No. 3 at day 70 following CAR T-cell infusion. The clinical outcomes including overall survival (OS) and adverse effects were evaluated up to date of May 12 2022. The OS at 180 days following CAR T-cell infusion was 66.67% (Fig. 5). Overall response rate (ORR) was 6/9 (66.67%).

Adverse Reactions During Gm-csf Administration

There were 4 patients who experienced fever while GM-CSF was administrated, of which two were GM-CSF related side effects, one was pneumonia and one was urinary tract infection.

From the first day of GM-CSF administration, patient #4 and #6 developed GM-CSF related fever without elevated cytokines and infection. Patient #4 experienced intermittent fever with highest temperatures up to 38.3℃ during GM-CSF treatment and patient #6 have a high temperature up to 38.4℃ during the first two days of the onset of GM-CSF administration. The patients’ body temperature was later dropped to normal range after physical cooling or loxoprofen sodium treatment. No cytokine release syndrome (CRS) or organ dysfunction or Immune Effector Cell-associated Neurotoxicity Syndrome (ICAN) was observed.

Infection occurred in two patients (2/9, 22.22%). One patient in this cohort (#2) had baseline leukopenia for 36 days and developed pneumonia for 6 days prior to GM-CSF administration (Table 1). The severity of the pneumonia in patient No. 2 was deteriorated from day 18 post-GM-CSF administration and the signs and symptoms of infection were alleviated two months later. In addition, another patient (#5) experienced mild urinary tract infection from day 5 post-GM-CSF administration.

It has been reported that there is 78% of patients developing Grade 3 or higher leukopenia in the ZUMA-1 trial [8]. It is recommended in NCCN guidelines that empiric broad-spectrum antibiotics, consider granulocyte colony-stimulating factor (G-CSF) if neutropenic after CAR T therapy. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are both hematopoietic CSFs, the administration of them can reduce the duration and severity of leukopenia for patients. G-CSF is a relatively specific stimulator of the growth and differentiation of hematopoietic progenitor cells committed to the neutrophil lineage. However, the activity of GM-CSF in stimulating production and activation is not restricted to neutrophils because it also affects monocytes and eosinophils [7]. Also, the application of GM-CSF is an immune adjuvant for its ability to increase dendritic cell (DC) maturation and function as well as macrophage activity. Although T cells do not possess a functional receptor for GM-CSF and thus do not rely on GM-CSF for proliferation and anti-tumor activity [9], one study in mice did show effect of GM-CSF on the anti-tumor properties of mouse CAR T-cell [10]. In another study, cancer cells transduced with an adenoviral vector carrying GM-CSF have induced strong antitumor immunity against tumor cells and prevented tumor regrowth in animal models [11]. Therefore, we try to use GM-CSF to treat leukopenia in order to gain better anti-tumor effect of CAR T-cell and better host immunity against infection. In this study, CAR T-cell expansion was observed in eight patients (8/9), including cerebrospinal fluid of one patient and PB of other seven patients. The peaks of CAR T-cell levels in PB appeared in day 7 (2–11) following the initiation of GM-CSF administration. And all patients experienced WBC recovery with GM-CSF. The median onset and duration time of WBC recovery were 9 (1–14) and 17(3–53) days following the initiation of GM-CSF administration. The OS at 180 days was 66.67% and ORR was 6/9 (66.67%) in patients with relapsed and refractory disease.

GM-CSF is also known to increase the proliferation and activation of macrophages and blood monocytes, increasing their pro-inflammatory properties during infection [12]. However, we find no significant difference observed in monocyte and CD3 + cell count at the baseline and 4-week follow-up. Our results showed white blood cell count in PB of nine patients gradually increased every week after GM-CSF administration. Also, the increment of neutrophil, lymphocyte and CD3-CD16 + CD56 + natural killer cell in PB was observed. The recovery of these cellular immunity improved anti-infective effects. Therefore, patient #5 whose infection occurred during GM-CSF using experienced mild symptoms and healed quickly. And patient #2 with baseline leukopenia 36 days before pneumonia diagnosis survived the life-threatening infection with administration of GM-CSF and augmented anti-infective therapy.

Of all the cytokines analyzed in the ZUMA-2 study, only peak levels of granzyme B and GM-CSF were associated with severe CRS and ICANS [13]. Then the major question that remains to be answered is how to avoid CRS during GM-CSF therapy. Sentman et al. reported specific CAR T-cell effector mechanisms and the host immune system are required for this cytokine release-like syndrome in murine models. Cytokine release syndrome required two key effector molecules in CAR T-cell: perforin and GM-CSF [10]. Moreover, Singh et al. demonstrated that GM-CSF is an exponential increase which secreted by monocyte-lineage cells upon CAR T-cell engagement of target tumor cells in vitro and in xenograft models [14]. Therefore, the optimal timing of supplemental with GM-CSF in a shortage of host immunity and CAR T-cell was chosen as avoidance of CRS. And in this study we verified that GM-CSF implemented at the right time will be required to boost the expansion of CAR T-cell without inducing CRS.

Upon tumor engagement, CAR T-cell secrete pro-inflammatory cytokines such as GM-CSF and IL-8, which promote the release of the major CRS biomarker IL-6 as well as IL-8, cytokines that were previously shown to be monocyte-dependent [14]. CRS biomarker release did not depend on physical contact between CAR T-cell and monocytes, suggesting that it may be possible to avoid CRS by lacking of sufficiently soluble factors involved in macrophage activation [9]. In this study, no significant increment of inflammatory markers was observed during GM-CSF administration. Moreover, the statistically significant decreases in the mean of cytokines (IL-17F, IL-1β, IL-4, TNF-α and TNF-β) and C-reactive protein (CRP) were seen during GM-CSF using. Data indicate that although GM-CSF levels are low in normal healthy individuals, activated lymphocytes produce elevated GM-CSF levels under pathologic conditions [15]. But our results demonstrated increased lymphocytes with the serum GM-CSF level in PB within the normal range during GM-CSF administration. Thus, no CRS or ICAN in this study was observed because sufficiently soluble factors were unavailable.

Treatment with CAR T-cell resulted in an increased ability of local macrophages to kill tumor cells, which enhanced the anti-tumor effects of CAR T-cell therapy at the tumor site [16]. GM-CSF increases macrophages’ responsiveness to CSF-1 (macrophage CSF) further enhancing the proliferation of resident macrophages in tissues [15]. Other study reported GM-CSF activates resident microglial cells within the CNS, promotes blood–brain barrier (BBB) breakdown, and enables inflammation by other immune cells [17]. Also, Sterner et al. reported that GM-CSF neutralization after CART19 reduced neuro-inflammation by 75% compared to CART19 plus isotype controls using human ALL blasts and human CART19 in this patient-derived xenograft mice model [5]. However, it is not clear that this result can apply to human. Actually, in our study CAR T expansion in the cerebrospinal fluid, not in peripheral blood, was observed without CRS during GM-CSF therapy (patient #8). This result may be interfered with the baseline 10Gy Whole-brain irradiation (WBI) 11 days prior to GM-CSF therapy and a second CAR T-cell infusion 2 days before GM-CSF administration. Therefore, further research is needed to confirm this finding.

Overall, we explored the timing of GM-CSF administration to play a role in CAR T-cell expansion and cellular immunity recovery without inducing CRS which facilitates to increase durable complete responses and decrease infection rates after CAR T therapy. On the basis of these results, this approach may improve the overall safety and efficacy of CAR T therapies for cancer patients and may eliminate the need for robust anti-infection treatment. Therefore, this study provides evidence for the clinical feasibility of combining CAR T-cell therapy with the GM-CSF to treat leukopenia patients with concomitant declination of circulating CAR T-cell.

CAR T: Chimeric antigen receptor T-cell; CRS: cytokine release syndrome; GM-CSF: Granulocyte-macrophage colony-stimulating factor; HSCT: hematopoietic stem cell transplantation; OS: overall survival; ICANS: immune effector cell-associated neurotoxicity syndrome; WBC: white blood cell counts; ANC: absolute neutrophil counts; PB: peripheral blood; ALL: acute lymphoblastic leukemia; Ph: philadelphia chromosome; DLBCL: diffuse large B cell lymphoma; LBL: lymphoblastic lymphoma; PMBL: primary mediastinal B cell lymphoma; PCNSL: primary central nervous system lymphoma; MRD: minimal residual disease; CNS: central nervous system; PD: progressive disease; SD: stable disease; PR: partial remission; NR: Non-remission; CR: complete remission with negative MRD; CR4: Fourth complete remission; FC: fludarabine and cyclophosphamide; CBV: cyclophosphamide bendamustine and etoposide; CRP: C-reactive protein; allo-HSCT: allogeneic hematopoietic stem cell transplant; auto-HSCT: autologous HSCT; ORR: Overall response rate; G-CSF: Granulocyte colony-stimulating factor; DC: dendritic cell; WBI :Whole-brain irradiation;

Ethics approval and consent to participate

The protocol for CAR T-cell therapies has been approved by the Hospital ethics committee.

Consent for publication

Not applicable

Availability of data and materials

Not applicable

Competing interests

AHC is a founding member of Shanghai YaKe Biotechnology Ltd., a biotechnology company focusing on research and development of tumor cellular immunotherapy. The remaining authors declare no conflict of interest.

Funding

Not applicable

Authors' contributions

YJ undertook the study design, treatment of patients, data analysis and wrote this paper. DF performed the material collection. CW helped to interpret the data and revised the manuscript. YZ helped in technical support and manufacture of CAR-T cells. CZ and SL participated in treatment of patients. YQ performed the laboratory examination. AHC helped in technical support and manufacture of CAR-T cells and revised the manuscript. ZJ undertook project design and data analysis. All authors read and approved the final manuscript.

Acknowledgements

Not applicable

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Table 1 is available in the Supplementary Files section

No competing interests reported.

table.xlsx

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posted 23 May, 2022

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Administration of Granulocyte-macrophage colony-stimulating factor enhanced CAR T-cell expansion and cellular immunity recovery without inducing cytokine release syndrome: a retrospective study

Status:

Version 1

Abstract

Figures

Introduction

Methods

Patient characteristics and study design

Gm-csf Treatment

Statistical analysis

Results

CAR T-cell expansion post-GM-CSF administration

The Increment Of White Blood Cells After Initial Gm-csf Administration

The Administration Of Gm-csf Alleviated Inflammation Indicators In Patients

Clinical Description Of Patients

Adverse Reactions During Gm-csf Administration

Discussion

Conclusion

Abbreviations

Declarations

References

Table

Competing Interests

Supplementary Files

Status:

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