Characterization of Extramedullary Disease in B-ALL and Response to CAR T-cell Therapy

Chimeric antigen receptor (CAR) T-cells effectively eradicate medullary B-cell acute lymphoblastic leukemia (B-ALL) and can traffic to and clear central nervous system (CNS) involvement. CAR T-cell activity in non¬contral nervous system (CNS) extramedullary disease (EMD) has not been well-characterized. We systematically evaluated CAR T-cell kinetics, associated toxicities, and efficacy in B-ALL non-CNS EMD. We conducted a retrospective review of B-ALL patients with non-CNS EMD who were screened for/enrolled on one of three CAR trials at our institution (CD19, CD22, CD19/22). Non-CNS EMD was identified by histology or radiographic imaging at extramedullary sites excluding the cerebrospinal fluid and CNS parenchyma. Of approximately 180 patients with relapsed/refractory B-ALL screened across multiple early phase trials over an 8-year period, 38 (21.1%) presented with isolated non-CNS EMD (n=5) or combined medullary/non-CNS EMD (n=33) on FDG PET-CT imaging. A subset receiving CAR T-cells (18 infusions) obtained FDG PET-CT scans pre- and post-infusion to monitor response. At best response, 72.2% (13 of 18) of patients demonstrated a medullary MRD-negative complete remission and complete (CR, n=7) or partial (PR, n=6) non-CNS EMD response. Non-CNS EMD responses to CAR T-cells were delayed (n=3) and residual non-CNS EMD was substantial; rarely, discrepant responses (marrow without EMD response) were observed (n=2). Unique CAR-associated toxicities at non-CNS EMD sites were seen in select patients. CAR T-cells are active in B-ALL non-CNS EMD. Still, non-CNS EMD response to CAR T-cells may be delayed and sub-optimal, particularly with multifocal disease. Serial FDG PET-CT scans are necessary for identifying and monitoring non-CNS EMD.

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Is autologous transplantation (autoHCT) in relapsed diffuse large B-cell lymphoma (DLBCL) patients achieving only a PET/CT positive partial remission (PR) appropriate in the CAR-T cell era?

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.8000 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 8000-8000 ◽

Cited By ~ 1

Author(s):

Nirav Niranjan Shah ◽

Kwang Woo Ahn ◽

Carlos Litovich ◽

Timothy Fenske ◽

Mehdi Hamadani

Keyword(s):

T Cells ◽

T Cell ◽

B Cell Lymphoma ◽

Study Cohort ◽

Risk Of Death ◽

Car T Cells ◽

Car T Cell ◽

Increased Risk ◽

Pet Ct ◽

Car T

8000 Background: In relapsed, chemosensitive DLBCL patients (pts), autoHCT consolidation is a standard therapy option. With the approval of anti-CD19 CAR T-cells in 2017, relapsed DLBCL pts with residual PET/CT avid disease after salvage therapies are increasingly being offered CAR T-cells in lieu of autoHCT. According to Center for International Blood and Marrow Transplant Research (CIBMTR) data in 2018, the number of autoHCT for DLBCL in the U.S. decreased by ~45% from prior years, likely due to application of CAR T-cells for both chemorefractory DLBCL and chemosensitive DLBCL pts not achieving a complete remission. Using the CIBMTR database, we report outcomes of autoHCT in relapsed chemosensitive DLBCL pts achieving only a PET/CT+ PR prior to HCT. Methods: 249 relapsed DLBCL pts undergoing an autoHCT from 2003-13 with a PET/CT+ PR prior to transplant were identified. The study cohort was divided into two groups: (a) early chemo-immunotherapy failure (ECF) defined as pts with primary refractory disease (PRefD) or relapse within 12 months of diagnosis, (b) late chemoimmunotherapy failure (LCF) defined as pts relapsing ≥12 months. Primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS) and relapse. Results: 182 pts had ECF and 67 pts had LCF. The median age of ECF pts was 57 years versus (vs) 63 years for LCF (p < 0.01). ECF pts more frequently had stage III-IV at diagnosis (74% vs 54%, p = < 0.01). 79% of ECF pts had PRefD. The most common conditioning regimen was BEAM in both cohorts. The adjusted 5-year probabilities for PFS and OS (ECF vs LCF) was not different between the 2 cohorts: 41% vs 41% (p = 0.93) and 51% vs 63% (p = 0.09), respectively. Cumulative incidence of relapse at 5 years in similar order was 48% vs 57%, p = 0.27. On multivariate analysis compared to the LCF, pts with ECF had an increased risk of death (HR = 1.61, 95%CI 1.05-2.46, p = 0.03) but no increased risk in PFS or relapse. Conclusions: Using the CIBMTR registry, we report outcomes of relapsed DLBCL pts in a PR with residual PET/CT avid disease at time of autoHCT. While OS favored LCF pts, the adjusted 5-year PFS (41%) was comparable in both cohorts. This 5 year PFS is comparable to results reported in historical trials of auto-HCT for DLBCL. With no randomized data demonstrating superiority of CAR T-cell therapy in chemosensitive PR patients, these findings strongly support that autoHCT should remain the current standard of care for this patient population.

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Quantification of Non-Hodgkin Lymphoma Disease Burden Using FDG PET-CT Helps Predict the Severity of Cytokine Release Syndrome

Blood ◽

10.1182/blood-2018-99-117983 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2997-2997

Author(s):

Jiasheng Wang ◽

Yongxian Hu ◽

Yanlei Zhang ◽

Guoqing Wei ◽

Huijun Xu ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Fdg Pet ◽

Disease Burden ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Pet Ct ◽

Car T ◽

Fdg Pet Ct

Abstract Background: CD19-targeting chimeric antigen receptor (CAR) T-cell therapy has shown great efficacy in patients with refractory/relapsed non-Hodgkin lymphoma (NHL), but was associated with serious adverse effects such as cytokine release syndrome (CRS). It has been speculated that NHL baseline disease burden might affect clinical outcome and CRS, but such assumption has not been explored in detail in previous studies. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG), calculated using FDG PET-CT, are quantitative indicators of baseline tumor burden. Methods: Utilizing FDG PET-CT, we calculated MTV and TLG at baseline and post CAR T-cell therapy in 15 patients with NHL. Results: Among all the patients, the median MTV was 72 (range 0.02-3024.9) cm3 and the median TLG was 610.1 (range 0.011-13156.3). After a median follow-up of 6 months, the overall response rate (ORR) was 66.7% (95% CI 38.4-88.2%). The baseline MTV and TLG did not have significant difference in patients with or without response (p=0.271 and 0.95, respectively). Cox-regression analysis did not find lower baseline MTV and TLG significantly associated with better overall survival (p=0.67 and 0.45, respectively). Patients with mild and moderate CRS (defined as Grade 0-2) had significantly lower MTV and TLG than those with severe CRS (Grade 3, 4) (median MTV: 49.3 v.s. 1137.7 cm3, p=0.012; median TLG: 379.1 v.s. 9384, p=0.012, Figure A, B). The median MTV in patients received tocilizumab, an IL-6 antagonist for the treatment of severe CRS, was 963.4 cm3, which was significantly higher than the patients not receiving tocilizumab (58.1 cm3, p=0.037). The median TLG in patients received tocilizumab was 9187.1, compared with 610.1 in patients not receiving tocilizumab (p=0.053). Using FDG PET-CT, we also demonstrated that CAR T-cell therapy in NHL patients could associate with severe local complications such as local compression and local inflammation. Conclusions: Low NHL baseline disease burden is not associated with better response rate or long-term outcome. Patients with higher baseline disease burden have more severe CRS Figure. Figure. Disclosures No relevant conflicts of interest to declare.

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Radiotherapy Is an Excellent Bridging Strategy in Large B-Cell Lymphoma Patients Selected for CAR T-Cell Therapy

Blood ◽

10.1182/blood-2021-151404 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2510-2510

Author(s):

Anne Niezink ◽

Jaap van Doesum ◽

Max Beijert ◽

Marcel Nijland ◽

Hans Langendijk ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

Fdg Pet ◽

Bridging Therapy ◽

T Cell Therapy ◽

Car T Cells ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Abstract Purpose/Objective Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has emerged as a potential curative treatment regime in patients with Large B-cell Lymphoma (LBCL) who have refractory or relapsed disease after two lines of systemic therapy. CAR T-cells are generated from autologous T-cells in specialized laboratories and the planning of the apheresis and manufacturing slot to the final infusion of the CAR T-cells into the patient may take up to 8 weeks for European centers, as the CAR T-cells are manufactured in the US. This logistic and time-consuming process might well be detrimental for patients with symptomatic and progressive disease. In these cases, bridging therapy may be indicated, referring to therapy administered after apheresis until CAR T-cell infusion. Early reports on radiotherapy (RT) as a bridging strategy have shown feasibility, safety, and effectivity, but patient numbers were limited. Here we present our experience with bridging therapy in patients selected for CAR T-cell therapy in a relatively large cohort. The current analysis focuses on the evaluation of safety and response rates. Material and Methods All patients treated with anti-CD19 CAR T-cell therapy are included in a prospective data registration program including data on patient and tumor characteristics, treatment, toxicity, and outcomes. All patients were treated with an anti-CD19 CAR containing a CD28 costimulatory molecule (Axi cel). For this analysis, patients with LBCL who underwent apheresis for CAR T-cell therapy were included. Bridging therapy consisted of steroids, chemotherapy, immunotherapy (systemic therapy; ST), RT, or a combination of these. Responses to bridging therapy were based on 18F-Fluordeoxyglucose PET (FDG-PET) before CAR T-cell infusion and Progression Free Survival (PFS), defined as time to clinical or FDG-PET based progression of disease, and Overall Survival (OS) are reported. Results In total, 49 patients underwent an apheresis procedure. Median follow-up after apheresis was 72 months. Sixteen of these patients (32.7%) did not receive bridging treatment, 19 (38.7%) underwent RT alone, 6 (12.2%) received ST alone and 8 (16.3%) received ST and RT. RT was given on bulky tumor or burdensome lesions, in most patients to a total dose of 20 Gy in 5 fractions (See figure). 81.5 percent of patients had an infield response to RT. 16 of 17 (94.1%) patients with multiple lesions, who received RT alone had out of field progression, compared to 75.0% in patients who received RT and ST and 60.0% after ST alone. No CTCAE v5.0 grade 2 or higher radiotherapy related toxicity was observed Finally, 45 patients (91.8%) received CAR T-cells, while 3 patients did not because of rapid progression and 1 patient due to no residual disease. On day 28, two patients had died due to progression. Of the remaining 43 patients, FDG-PET evaluation showed progressive disease in 7 (16.3%) patients, stable disease in one patient (2.3%), partial response in 12 (27.9%) , and complete response in 23 (53.5%). The 2-year PFS of patients who did not receive bridging treatment was 47%, compared to 49% in patients bridged with RT alone and 31% in patients treated with ST or combined treatment. The 2-year OS was 63% versus 46%, and 34%, respectively. Conclusion Bridging the time between apheresis and CAR T-cell infusion is a critical phase in CAR T-cell therapy. Selection of bridging treatment type is based on prior treatment, tumor load and symptoms. RT is an excellent bridging option with a high local control rate and favorable toxicity profile and should be considered in this heavily pre-treated patient population. Figure 1 Figure 1. Disclosures Van Meerten: Kite, a Gilead Company: Honoraria; Janssen: Consultancy.

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[18F]FDG PET-CT in Patients With DLBCL Treated With CAR-T Cell Therapy: A Practical Approach of Reporting Pre- and Post-treatment Studies

10.21203/rs.3.rs-749949/v1 ◽

2021 ◽

Author(s):

Dan Cohen ◽

Efrat Luttwak ◽

Ofrat Beyar-Katz ◽

Shir Hazut Krauthammer ◽

Yael Bar-On ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Fdg Pet ◽

B Cell Lymphoma ◽

Ct Scans ◽

T Cell Therapy ◽

Deauville Score ◽

Pet Ct ◽

Car T ◽

Fdg Pet Ct

Abstract Purpose: The introduction of CD19-specific chimeric antigen receptor T-cell therapy (CAR-T) for treatment of relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL) gives hope to patients with otherwise dismal prognosis. Therapy outcomes depend, however, on selection of patients and on accurate early identification of non-responders. Patients treated with CAR-T usually undergo [18F]FDG PET-CT at time of decision (TD), time of CAR-T transfusion (TT), one month (M1) and three months (M3) post therapy. The purpose of the current study was to identify the specific parameters that should be addressed when reporting PET-CT studies in the clinical setting of CAR-T therapy.Methods: A total of 138 PET-CT scans (30 TD, 42 TT, 44 M1, 22 M3) of 48 patients treated with CAR-T were included. SUVmax, TMTV, TLG were calculated in all scans. Response was assessed using Deauville scale and ΔSUVmax method. Overall survival (OS) was the primary endpoint. Median follow-up was 12.8 (IQR 6.4-16.0) months from CAR-T infusion.Results: In a univariate analysis, TD-SUVmax > 17.1 and TT-SUVmax > 12.1 were associated with shorter OS (Pv<0.05). In a multivariate analysis, three factors were significantly associated with shorter OS: TD-SUVmax > 17.1 (HR 10.3; Pv<0.01), LDH > 450 U/l (HR 7.7; Pv<0.01) and ECOG score > 1 (HR 5.5; Pv=0.04). Data from TD and TT PET-CT scans were not predictive of toxicity. On M1-PET-CT, patients with Deauville score > 3 had significantly shorter OS (median 7.9 months, versus not reached, Pv<0.01). ΔSUVmax ≤ 66% on M1-PET-CT predicted shorter OS when comparison of M1-SUVmax was made to TD-SUVmax (Pv=0.02) and not to TT-SUVmax (Pv=0.38).Conclusion: Pre-treatment SUVmax may guide patient selection for CAR-T therapy. On M1-PET-CT, Deauville score and ΔSUVmax from TD may identify early therapy failure. These parameters are easy to obtain and should be included in the PET-CT report.

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Up-Regulation of CAR-T Cells after G-CSF and Dexamethasone Treatment in a Defuse Large B Cell Lymphoma Patient Receiving 4SCAR19 T Cell Therapy

Blood ◽

10.1182/blood.v126.23.5130.5130 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5130-5130

Author(s):

Hongmei Jing ◽

Lung-Ji Chang ◽

Mingyi Chen ◽

Fang Bao ◽

Jing Wang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Lymph Nodes ◽

Peripheral Blood ◽

Whole Body ◽

Dexamethasone Treatment ◽

Car T Cells ◽

Car T Cell ◽

Pet Ct ◽

Car T

Abstract A 37-year-old woman was diagnosed with DLBCL, GCB origin, positive with CD20, Bcl-2, Bcl-6, CD10 and negative with CD3, CD5, ,D21, CD23, CyclinD1. PET-CT scan showed that her lymph nodes were broadly involved. Based on PET-CT, the stage was IIIA and aaIPI score was 1. After eight cycles of R-CHOP (rituximab, cyclophosphamide, epirubicin, vincristine, and prednisone), the tumor regressed to a small retroperitoneum lesion with SUV 2.0, and she received another four cycles of rituximab for maintenance. The tumor relapsed one year later with resistance to ESHAP after she had failed multiple alternative treatments including GA101 trial, 3x DICE, MTX1g, 2x GEMOX, and 2x EPOCH. She was enrolled in a CD19-CAR (chimeric antigen receptor) T cell pilot study in January 2015. Her T cells were apheresis collected and transduced with a 4th generation, apoptosis-inducible, safety-engineered lentiviral CAR: CD19- scFv/CD28/CD137/CD27/CD3ζ-iCasp9 (4SCAR19). A personalized conditioning regimen was given based on the patient's history to chemotherapy: cyclophosphamide 500mg/d d1-3, and fludarabine 50mg/d d1-4, 40mg d5. Two days later, she received infusions of a total dose of 1.27×108 of the 4SCAR19 T cells (2x106/kg). At day 7 (D7) after infusion, she developed a fever over 39o C, which lasted for 7 days; this was controlled with NSAIDs (Non-Steroidal Anti-inflammatory Drugs). The tumor in her lymph nodes began to shrink 5 days after CAR-T infusion and she achieved nCR (near complete response) after 30 days. In a follow up PET/CT 3 months after CAR-T infusion, there was only one suspected retroperitoneum lesion (SUV 3.8) in the whole body, but it was indiscernable whether the SUV signal was tumor or T cell related. We monitored the peripheral blood CAR-T cell counts by qPCR and detected 0.03%, 0.07%, 0.3%, 9.3%, 0.01%, 1.57% on D7, D13, D48, D69, D84 and D112, respectively. In attempt to perform an autotransplantation to pursue a cure, she was mobilized twice with G-CSF on D68-D72, D110-112, plus dexamethasone 20mg/d on D101-102 and 15 mg/d on D110-111. Unexpectedly, the CAR-T cells in the patient peripheral blood increased to 9% after the first mobilization, and to 18% after the second mobilization. To this date, the patient has remained in nCR after 4SCAR19 therapy (January 23 to July 23, 2015). To our knowledge, this is the first report of evident CAR-T cell boost associated with G-CSF plus dexamethasone treatment. Further investigation is warranted to understand the molecular mechanisms behind such a favorable CAR-T therapy outcome in a terminal DLBCL disease. Disclosures Kuo: America Yuva Biomed: Employment. Liu:America Yuva Biomed: Employment. Dong:America Yuva Biomed: Consultancy.

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Chimeric Antigen Receptor-Engineered T-Cells - A New Way and Era for Lymphoma Treatment

Recent Patents on Anti-Cancer Drug Discovery ◽

10.2174/1574892814666191022164641 ◽

2020 ◽

Vol 14 (4) ◽

pp. 312-323

Author(s):

Romeo G. Mihăilă

Keyword(s):

T Cells ◽

T Cell ◽

Response Rate ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Car T Cells ◽

Future Developments ◽

Car T Cell ◽

Large B Cell Lymphoma ◽

Car T

Background: Patients with refractory or relapsed diffuse large B-cell lymphoma have a poor prognosis with the current standard of care. Objective: Chimeric Antigen Receptor T-cells (CAR T-cells) are functionally reprogrammed lymphocytes, which are able to recognize and kill tumor cells. The aim of this study is to make progress in this area. Method: A mini-review was achieved using the articles published in Web of Science and PubMed in the last year and the new patents were made in this field. Results: The responses to CAR T-cell products axicabtagene ciloleucel and tisagenlecleucel are promising; the objective response rate can reach up to 83%, and the complete response rate ranges between 40 and 58%. About half of the patients may have serious side effects, such as cytokine release syndrome and neurotoxicity. Current and future developments include the improvement of CAR T-cell expansion and polyfunctionality, the combined use of CAR T-cells with a fusion protein between interferon and an anti-CD20 monoclonal antibody, with checkpoint inhibitors or small molecule sensitizers that have apoptotic-regulatory effects. Furthermore, the use of IL-12-expressing CAR T-cells, an improved technology for the production of CAR T-cells based on targeted nucleases, the widespread use of allogeneic CAR T-cells or universal CAR T-cells obtained from genetically engineered healthy donor T-cells are future developments actively considered. Conclusion: CAR T-cell therapy significantly improved the outcome of patients with relapsed or refractory diffuse large B-cell lymphoma. The advances in CAR T-cells production technology will improve the results and enable the expansion of this new immunotherapy.

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Structure of the Signal Transduction Domain in Second-Generation CAR Regulates the Input Efficiency of CAR Signals

International Journal of Molecular Sciences ◽

10.3390/ijms22052476 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2476

Author(s):

Kento Fujiwara ◽

Masaki Kitaura ◽

Ayaka Tsunei ◽

Hotaka Kusabuka ◽

Erika Ogaki ◽

...

Keyword(s):

Signal Transduction ◽

T Cells ◽

T Cell ◽

Second Generation ◽

Independent Manner ◽

Cell Functions ◽

Car T Cells ◽

Car T Cell ◽

Car T ◽

The Impact

T cells that are genetically engineered to express chimeric antigen receptor (CAR) have a strong potential to eliminate tumor cells, yet the CAR-T cells may also induce severe side effects due to an excessive immune response. Although optimization of the CAR structure is expected to improve the efficacy and toxicity of CAR-T cells, the relationship between CAR structure and CAR-T cell functions remains unclear. Here, we constructed second-generation CARs incorporating a signal transduction domain (STD) derived from CD3ζ and a 2nd STD derived from CD28, CD278, CD27, CD134, or CD137, and investigated the impact of the STD structure and signaling on CAR-T cell functions. Cytokine secretion of CAR-T cells was enhanced by 2nd STD signaling. T cells expressing CAR with CD278-STD or CD137-STD proliferated in an antigen-independent manner by their STD tonic signaling. CAR-T cells incorporating CD28-STD or CD278-STD between TMD and CD3ζ-STD showed higher cytotoxicity than first-generation CAR or second-generation CARs with other 2nd STDs. The potent cytotoxicity of these CAR-T cells was not affected by inhibiting the 2nd STD signals, but was eliminated by placing the STDs after the CD3ζ-STD. Our data highlighted that CAR activity was affected by STD structure as well as by 2nd STD signaling.

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Anti-Mesothelin CAR T cell therapy for malignant mesothelioma

Biomarker Research ◽

10.1186/s40364-021-00264-1 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Laura Castelletti ◽

Dannel Yeo ◽

Nico van Zandwijk ◽

John E. J. Rasko

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

Malignant Mesothelioma ◽

Oncolytic Viruses ◽

T Cell Therapy ◽

Car T Cells ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

AbstractMalignant mesothelioma (MM) is a treatment-resistant tumor originating in the mesothelial lining of the pleura or the abdominal cavity with very limited treatment options. More effective therapeutic approaches are urgently needed to improve the poor prognosis of MM patients. Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a novel potential treatment for this incurable solid tumor. The tumor-associated antigen mesothelin (MSLN) is an attractive target for cell therapy in MM, as this antigen is expressed at high levels in the diseased pleura or peritoneum in the majority of MM patients and not (or very modestly) present in healthy tissues. Clinical trials using anti-MSLN CAR T cells in MM have shown that this potential therapeutic is relatively safe. However, efficacy remains modest, likely due to the MM tumor microenvironment (TME), which creates strong immunosuppressive conditions and thus reduces anti-MSLN CAR T cell tumor infiltration, efficacy and persistence. Various approaches to overcome these challenges are reviewed here. They include local (intratumoral) delivery of anti-MSLN CAR T cells, improved CAR design and co-stimulation, and measures to avoid T cell exhaustion. Combination therapies with checkpoint inhibitors as well as oncolytic viruses are also discussed. Preclinical studies have confirmed that increased efficacy of anti-MSLN CAR T cells is within reach and offer hope that this form of cellular immunotherapy may soon improve the prognosis of MM patients.

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CARTmath—A Mathematical Model of CAR-T Immunotherapy in Preclinical Studies of Hematological Cancers

Cancers ◽

10.3390/cancers13122941 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2941

Author(s):

Luciana R. C. Barros ◽

Emanuelle A. Paixão ◽

Andrea M. P. Valli ◽

Gustavo T. Naozuka ◽

Artur C. Fassoni ◽

...

Keyword(s):

Mathematical Model ◽

T Cells ◽

T Cell ◽

Mouse Models ◽

In Silico ◽

Car T Cells ◽

Car T Cell ◽

Cell Immunotherapy ◽

Car T ◽

T Cell Immunotherapy

Immunotherapy has gained great momentum with chimeric antigen receptor T cell (CAR-T) therapy, in which patient’s T lymphocytes are genetically manipulated to recognize tumor-specific antigens, increasing tumor elimination efficiency. In recent years, CAR-T cell immunotherapy for hematological malignancies achieved a great response rate in patients and is a very promising therapy for several other malignancies. Each new CAR design requires a preclinical proof-of-concept experiment using immunodeficient mouse models. The absence of a functional immune system in these mice makes them simple and suitable for use as mathematical models. In this work, we develop a three-population mathematical model to describe tumor response to CAR-T cell immunotherapy in immunodeficient mouse models, encompassing interactions between a non-solid tumor and CAR-T cells (effector and long-term memory). We account for several phenomena, such as tumor-induced immunosuppression, memory pool formation, and conversion of memory into effector CAR-T cells in the presence of new tumor cells. Individual donor and tumor specificities are considered uncertainties in the model parameters. Our model is able to reproduce several CAR-T cell immunotherapy scenarios, with different CAR receptors and tumor targets reported in the literature. We found that therapy effectiveness mostly depends on specific parameters such as the differentiation of effector to memory CAR-T cells, CAR-T cytotoxic capacity, tumor growth rate, and tumor-induced immunosuppression. In summary, our model can contribute to reducing and optimizing the number of in vivo experiments with in silico tests to select specific scenarios that could be tested in experimental research. Such an in silico laboratory is an easy-to-run open-source simulator, built on a Shiny R-based platform called CARTmath. It contains the results of this manuscript as examples and documentation. The developed model together with the CARTmath platform have potential use in assessing different CAR-T cell immunotherapy protocols and its associated efficacy, becoming an accessory for in silico trials.

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Adoptive Immunotherapy beyond CAR T-Cells

Cancers ◽

10.3390/cancers13040743 ◽

2021 ◽

Vol 13 (4) ◽

pp. 743

Author(s):

Aleksei Titov ◽

Ekaterina Zmievskaya ◽

Irina Ganeeva ◽

Aygul Valiullina ◽

Alexey Petukhov ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Solid Tumors ◽

Adoptive Immunotherapy ◽

Γδ T Cells ◽

Car T Cells ◽

Car T Cell ◽

Cell Immunotherapy ◽

Car T

Adoptive cell immunotherapy (ACT) is a vibrant field of cancer treatment that began progressive development in the 1980s. One of the most prominent and promising examples is chimeric antigen receptor (CAR) T-cell immunotherapy for the treatment of B-cell hematologic malignancies. Despite success in the treatment of B-cell lymphomas and leukemia, CAR T-cell therapy remains mostly ineffective for solid tumors. This is due to several reasons, such as the heterogeneity of the cellular composition in solid tumors, the need for directed migration and penetration of CAR T-cells against the pressure gradient in the tumor stroma, and the immunosuppressive microenvironment. To substantially improve the clinical efficacy of ACT against solid tumors, researchers might need to look closer into recent developments in the other branches of adoptive immunotherapy, both traditional and innovative. In this review, we describe the variety of adoptive cell therapies beyond CAR T-cell technology, i.e., exploitation of alternative cell sources with a high therapeutic potential against solid tumors (e.g., CAR M-cells) or aiming to be universal allogeneic (e.g., CAR NK-cells, γδ T-cells), tumor-infiltrating lymphocytes (TILs), and transgenic T-cell receptor (TCR) T-cell immunotherapies. In addition, we discuss the strategies for selection and validation of neoantigens to achieve efficiency and safety. We provide an overview of non-conventional TCRs and CARs, and address the problem of mispairing between the cognate and transgenic TCRs. Finally, we summarize existing and emerging approaches for manufacturing of the therapeutic cell products in traditional, semi-automated and fully automated Point-of-Care (PoC) systems.

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