Chimeric Antigen Receptor Cell Therapy Research Articles

Beyond Chemoimmunotherapy in Advanced Non-Small Cell Lung Cancer: New Frontiers, New Challenges.

Chemoimmunotherapy is currently the preferred first-line treatment option for the majority of patients with advanced non-small cell lung cancer without driver genetic alterations. Most of these patients, however, will experience disease progression within the first year after treatment initiation and both patients and their physicians will be confronted with the dilemma of the optimal second-line treatment. Identification of molecular targets, such as KRASG12C, BRAFV600X, METexon14, and human epidermal growth factor receptor 2 mutations, and RET rearrangements offer therapeutic opportunities in pretreated patients with corresponding alterations. For those tumors that do not harbor oncogenic drivers, second-line treatment with docetaxel remains the current standard of care despite modest efficacy. Strategies to challenge docetaxel include the combination of immune checkpoint inhibitors (ICIs) with tyrosine inhibitors of multiple kinases or with DNA damage response inhibitors, antibody-drug conjugates, and locoregional treatments for oligoprogressive disease. Next-generation immunotherapy strategies, such as T-cell engagers, immune-mobilizing monoclonal T-cell receptors, chimeric antigen receptor cell therapy, tumor infiltrating lymphocytes, and T-cell receptor cell therapy are being currently investigated in the quest to reverse resistance to ICIs. Importantly, the advent of these new agents heralds a novel spectrum of toxicities that require both the physician's and the patient's education. Herein, we review current and future strategies aiming to outperform docetaxel after chemoimmunotherapy failure, and we provide practical information on how to best communicate to our patients the unique toxicity aspects associated with immunotherapy.

Enrichment of T-lymphocytes from leukemic blood using inertial microfluidics toward improved chimeric antigen receptor-T cell manufacturing

Chimeric antigen receptor cell therapy is a successful immunotherapy for the treatment of blood cancers. However, hurdles in their manufacturing remain including efficient isolation and purification of the T-cell starting material. Herein, we describe a one-step separation based on inertial spiral microfluidics for efficient enrichment of T-cells in B-cell acute lymphoblastic leukemia (ALL) and B-cell chronic lymphocytic leukemia patient's samples. In healthy donors used to optimize the process, the lymphocyte purity was enriched from 65% (SD ± 0.2) to 91% (SD ± 0.06) and T-cell purity was enriched from 45% (SD ± 0.1) to 73% (SD ± 0.02). Leukemic samples had higher starting B-cells compared to the healthy donor samples. Efficient enrichment and recovery of lymphocytes and T-cells were achieved in ALL samples with B-cells, monocytes and leukemic blasts depleted by 80% (SD ± 0.09), 89% (SD ± 0.1) and 74% (SD ± 0.09), respectively, and a 70% (SD ± 0.1) T-cell recovery. Chronic lymphocytic leukemia samples had lower T-cell numbers, and the separation process was less efficient compared to the ALL. This study demonstrates the use of inertial microfluidics for T-cell enrichment and depletion of B-cell blasts in ALL, suggesting its potential to address a key bottleneck of the chimeric antigen receptor-T manufacturing workflow.

The use of T-cells with chimeric antigen receptor (CAR-T) in combination with chemotherapy and radiotherapy for the treatment of solid tumors

The introduction of chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematological diseases, particularly in combating blood cancer. The success of this cell therapy approach has led to the development of approximately seven commercial CAR-T based drugs. However, the application of CAR-T therapy for solid tumors has proven to be less effective due to challenges such as the varied antigens in solid tumors, an immunosuppressive tumor environment, limited immune cell infiltration, reduced CAR-T cell activity and toxicity issues. To solve these problems, scientists are making efforts to improve and improve the methods of treatment of solid tumors. Chemotherapy is the standard treatment for a large number of malignant neoplasms. It is also used before starting cell therapy for lymphodepletion and better engraftment of injected CAR-T cells. It has been shown that chemotherapy can reduce the immunosuppressive effect of the tumor microenvironment, destroy the stroma, and promote better infiltration of the tumor by CAR-T cells, improving their survival, persistence, cytotoxicity, and influencing the metabolism of immune cells inside the tumor. The effectiveness of combining chemotherapy and CAR-T cell therapy relies on various factors such as tumor type, dosage, treatment schedule, CAR-T cell composition, and individual biological traits. Similarly, radiation therapy can enhance tumor cell vulnerability to specific treatments while also supporting tumor cell survival.In this review, we discuss the use of CAR-T therapy to combat solid tumors, regarding the challenges of treating solid tumors, ways to overcome them, and also touch upon the possibility of using combination treatments to improve the effectiveness of cell therapy.

Advanced strategies in improving the immunotherapeutic effect of CAR-T cell therapy.

Chimeric antigen receptor (CAR-T) cell therapy is a newly developed immunotherapy strategy and has achieved satisfactory outcomes in the treatment of hematological malignancies. However, some adverse effects related to CAR-T cell therapy have to be resolved before it is widely used in clinics as a cancer treatment. Furthermore, the application of CAR-T cell therapy in the treatment of solid tumors has been hampered by numerous limitations. Therefore, it is essential to explore novel strategies to improve the therapeutic effect of CAR-T cell therapy. In this review, we summarized the recently developed strategies aimed at optimizing the generation of CAR-T cells and improving the anti-tumor efficiency of CAR-T cell therapy. Furthermore, the discovery of new targets for CAR-T cell therapy and the combined treatment strategies of CAR-T cell therapy with chemotherapy, radiotherapy, cancer vaccines and nanomaterials are highlighted.

CAR-T Cell Therapy in B-Cell Acute Lymphoblastic Leukemia.

Treatment of refractory and relapsed (R/R) B acute lymphoblastic leukemia (B-ALL) is an unmet medical need in both children and adults. Studies carried out in the last two decades have shown that autologous T cells engineered to express a chimeric antigen receptor (CAR-T) represent an effective technique for treating these patients. Antigens expressed on B-cells, such as CD19, CD20, and CD22, represent targets suitable for treating patients with R/R B-ALL. CD19 CAR-T cells induce a high rate (80-90%) of complete remissions in both pediatric and adult R/R B-ALL patients. However, despite this impressive rate of responses, about half of responding patients relapse within 1-2 years after CAR-T cell therapy. Allo-HSCT after CAR-T cell therapy might consolidate the therapeutic efficacy of CAR-T and increase long-term outcomes; however, not all the studies that have adopted allo-HSCT as a consolidative treatment strategy have shown a benefit deriving from transplantation. For B-ALL patients who relapse early after allo-HSCT or those with insufficient T-cell numbers for an autologous approach, using T cells from the original stem cell donor offers the opportunity for the successful generation of CAR-T cells and for an effective therapeutic approach. Finally, recent studies have introduced allogeneic CAR-T cells generated from healthy donors or unmatched, which are opportunely manipulated with gene editing to reduce the risk of immunological incompatibility, with promising therapeutic effects.

Current Status and Progress of CAR-T Cell Therapy in the Treatment of Small Cell Lung Cancer

Small cell lung cancer (SCLC), which takes possession of about 15% of lung cancers, is closely related to smoking and is more common in older men. It has a high degree of malignancy, rapid growth, early metastasis, low survival rate in five years, and unfavorable prognosis. Current treatments include targeted therapy, chemotherapy and immunotherapy, etc. Among them, immunotherapy has grown in popularity as a new technique these years for treating tumors in the overall setting of SCLC. The chimeric antigen receptor (CAR-T) cell therapy, which has already showed considerable success curing hematological malignancies, has attracted the attention of many scientists. According to the current experimental studies, CD56, DLL3, GD2, CD133/AC133, CDH17 and other CAR-T cell targets have been found. AMG 119, a DLL3-targeted CAR T-cell therapy, has successfully completed phase I clinical trial and demonstrated good efficacy. Because of the limiting factors of CAR-T such as antigen escape, cancer infiltration, CAR-T cell trafficking, immunosuppressive microenvironment and on-target, off-tumor effects, etc. Further research and exploration are still needed in the field of solid tumor application. In order to effectively treat SCLC, there was still a huge progress to be made for CAR-T cell therapy compared to conventional therapy approaches. Further basic research and clinical studies are required.

CAR-T treatment for cancer: prospects and challenges.

Chimeric antigen receptor (CAR-T) cell therapy has been widely used in hematological malignancies and has achieved remarkable results, but its long-term efficacy in solid tumors is greatly limited by factors such as the tumor microenvironment (TME). In this paper, we discuss the latest research and future views on CAR-T cell cancer immunotherapy, compare the different characteristics of traditional immunotherapy and CAR-T cell therapy, introduce the latest progress in CAR-T cell immunotherapy, and analyze the obstacles that hinder the efficacy of CAR-T cell therapy, including immunosuppressive factors, metabolic energy deficiency, and physical barriers. We then further discuss the latest therapeutic strategies to overcome these barriers, as well as management decisions regarding the possible safety issues of CAR-T cell therapy, to facilitate solutions to the limited use of CAR-T immunotherapy.

The Impact of Social Determinants of Health on Brexucabtagene Autoleucel Outcomes in Adults with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia

Background Brexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR-T) cell therapy that recently received U.S. FDA approval as the first CAR-T cell therapy for adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). Social determinants of health (SDoH) are shown to significantly influence outcomes in B-ALL. However, how SDoH relate to and affect outcomes in patients with B-ALL receiving CAR-T therapy has not been well established. We studied the impact of SDoH on outcomes of adults with B-ALL receiving brexu-cel as part of the Real-world Outcomes Collaborative of CAR-T in Adult ALL (ROCCA). Methods This retrospective multicenter analysis spanning 25 U.S centers included adults (≥18 years) with r/r B-ALL treated with commercial brexu-cel between 2021-2023. Progression-free survival (PFS) and overall survival (OS) were calculated from the day of brexu-cel infusion and were not censored for hematopoietic cell transplant (HCT) or maintenance. Univariate and multivariate Cox proportional hazards models were used to evaluate the association of age, sex, pre-apheresis disease burden, and SDoH (referral source, insurance, distance from home to CAR-T site, marital status, and the social deprivation index) with progression-free survival (PFS) and overall survival (OS). The social deprivation index (SDI), a composite measure (including income, education, employment, housing, household characteristics, and transportation) used to quantify socio-economic variation in health outcomes, with higher SDI indicating greater social disadvantage, was estimated at the zip code level. (Butler et al., 2013) Results Of the 152 patients who received brexu-cel (Table 1), 57% were male. 51% identified as non-Hispanic White, with the remainder identifying as Hispanic (34%), Asian/Pacific Islander (7%), Black (6%), American Indian/Alaskan Native (1%), or mixed race (1%). A majority (46%) were referred for brexu-cel from private/community-based practices and 62% lived within 50 miles of the CAR-T center (36% lived >50 miles and 2% were unknown). Health insurance coverage included primarily public (49%) and private (42%); no patients were uninsured. High SDI (76-100% percentile) was present in 26%, while 14% had a low SDI (0-25 th percentile). In unadjusted analyses, there was no difference in PFS or OS between patients with high versus low SDI; closer distance to the CAR-T site (<50 miles versus >50 miles)) was associated with worse OS (HR 1.96; 95% CI 1.00, 3.84; p=0.05). Multivariate analysis (Table 2) revealed that male sex was associated with inferior PFS (HR 1.98; 95% CI 1.02, 3.85; p=0.04) and OS (HR 2.52; 95% CI 1.09, 5.84; p=0.03). There was no difference in PFS (HR 0.95, 95% CI 0.48-1.88, p=0.88) or OS (HR 0.80; 95% CI 0.33,1.92; p=0.62) when comparing Hispanic and non-Hispanic White patients. Additionally, there was no difference in PFS or OS based on any SDoH, including insurance type, marital status, referral source, caregiver type, and distance to transplant center. Conclusions In patients receiving brexu-cel, survival outcomes appear independent of SDoH. Contrary to previous reports suggesting inferior outcomes for Hispanic patients with B-ALL after receiving traditional systemic therapies, we observed comparable outcomes to non-Hispanic patients treated with brexu-cel. Distance from the CAR-T site and referrals from the community did not affect outcomes. Additionally, those with higher SDI had similar outcomes to those with a lower SDI, although this analysis was limited by sample size and the selection bias that exists in being referred for brexu-cel in the first place. The relatively lower logistical burden of CAR-T compared to allogeneic stem cell transplant or non-fixed duration systemic therapies may have mitigated the impact of SDoH on outcomes. These real-world data suggest that continuing to improve access to and treatment with brexu-cel may improve overall outcomes for disadvantaged populations with r/r B-ALL.

Two-Year Follow-up Results of C-CAR066, a Novel Anti-CD20 Chimeric Antigen Receptor Cell Therapy (CAR-T) in Relapsed or Refractory (r/r) Large B-Cell Lymphoma (LBCL) Patients after Failure of CD19 CAR-T Therapy

Background: Disease recurrence or progression represents a significant challenge in r/r LBCL treated with CAR-T. In a large analysis of r/r LBCL pts who receive further therapy after CD19 CAR-T treatment failure, the overall response rate (ORR) is 39% (CR 20%; PR 19%) and the median post-treatment-OS and post-treatment-EFS are 8.5 months and 1.9 months respectively. C-CAR066 is a novel 2nd generation CAR-T therapy targeting CD20 antigen. We previously reported that C-CAR066 had shown a favorable safety profile and promising efficacy in pts with r/r LBCL following failure to CD19 CAR-T therapy. At a median follow-up of 4.2 months, the ORR was 100%, with 70.0% (7/10) achieving complete response (CR) (Liang et al. ASCO 2021. #2508). Here we present the updated results to include more pts (n=14) and a longer follow-up period. Methods: This first-in-human (FIH) study is an open-label, dose-finding, phase 1 investigator-initiated trial (IIT) to determine the safety and efficacy of C-CAR066 in r/r LBCL (including DLBCL, tFL and PMBCL) after previous CD19 CAR T-cell treatment failure. This study was conducted at two clinical sites in China. C-CAR066 was administered at doses of 2.0x10 6 CAR-T cells/kg and 3.0x10 6 CAR-T cells/kg after a 3-day conditioning chemotherapy. The primary objective was to assess the safety and tolerability of C-CAR066. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to ASTCT 2019 criteria. The secondary objectives were to evaluate C-CAR066 efficacy and pharmacokinetics (PK). Response was assessed per Lugano 2014 criteria. The study follow-up period was 2 years. Results: Between Oct 16, 2019, and Aug 17, 2021, a total of 14 pts received C-CAR066. 11 pts (78.6%) were DLBCL, 3 pts (21.4%) were tFL. The median age was 54.5 years (range, 37-67) with 2 pts (14.3%) ≥65 years. 12 pts (85.7%) were in Ann Arbor Stage III/IV. 7 pts (50.0%) were double-expressor lymphoma. Median number of prior lines of therapy was 5 (range, 2-7). All pts had prior CAR-T therapy, which included CD19 CAR-T (12 pts), CD19/CD22 bispecific CAR-T (1 pts), and CD19/CD79b bispecific CAR-T (1 pts). 12 pts responded to the prior CAR-T therapy (2 CR and 10 PR), and the median duration of response (DOR) was 1.5 months. Median time from prior CAR-T to C-CAR066 infusion were 5.45 months (range, 3.4-14.2). 7 pts (50.0%) received bridging therapy. As of Jan 15, 2023, 12/14 pts (85.7%) experienced CRS, all were grade 1/2, except for 1 pt dosed at 3.0×10 6 CAR- T cells/kg experienced a grade ≥3 CRS. This pt recovered after receiving corticosteroids and tocilizumab. The median time to CRS onset was 5.5 days (range, 2-15), and the median time to resolution was 4.0 days (range, 1-15). No pts experienced ICANS. Grade ≥3 neutropenia, anemia, thrombocytopenia, and infection were reported in 92.9%, 50.0%, 21.4% and 14.3% of pts, respectively. No new safety signals were observed in this updated 2-year follow-up. Investigator assessed ORR was 92.9%, with 57.1% CR. Median time to first response and CR were 1.0 month (range, 0.9-2.8) and 2.5 month (range, 1.0-2.8), respectively. With the median follow-up of 19.5 months, median PFS and DOR were 9.4 months and 8.3 months, respectively. 5 pts remained in CR 12 months after infusion, and 4 of them remained in CR after 24 months. 6 deaths occurred due to progressive disease. Median post-treatment-OS had not been reached at 24 months. 13 of 14 pts had assessable PK and pharmacodynamic data (one pt dropped out before day 28). The median T max was 11 days (range, 10-23), the median C max was 398,996 copies/µg gDNA (range, 51,667-1,286,932), and the median AUC 0-28day of 4,437,474 copies/µg∙day (range, 431,534-17,842,217), the median T last was 59 days (21~571). We have observed that C-CAR066 can effectively expand and eliminate CD19+/CD20+ B cells in patients. The median time to B cell depletion was 5.5 days (range, 4-11). B cell recovery was observed in 6 (46.2%) pts from 53 to 366 days after the C-CAR066 infusion, 3 of them remained in CR by the data cutoff date. Conclusions: Longer term follow-up demonstrated that C-CAR066 can produce a deep and durable response with a favorable safety profile in pts with r/r LBCL who failed prior CD19 CAR-T therapy.

CXCR4-modified CAR-T cells suppresses MDSCs recruitment via STAT3/NF-κB/SDF-1α axis to enhance efficacy against pancreatic cancer

Claudin18.2 (CLDN18.2)-specific chimeric antigen receptor (CAR-T) cells displayed limited efficacy in CLDN18.2-positive pancreatic ductal adenocarcinoma (PDAC). Strategies are needed to improve the trafficking capacity of CLDN18.2-specific CAR-T cells. PDAC has a unique microenvironment that consists of abundant cancer-associated fibroblasts (CAFs), which could secrete stromal cell-derived factor 1α (SDF-1α), the ligand of CXCR4. Then, we constructed and explored CLDN18.2-targeted CAR-T cells with CXCR4 co-expression in treating immunocompetent mouse models of PDAC. The results indicated that CXCR4 could promote the infiltration of CAR-T cells and enhance their efficacy invivo. Mechanistically, the activation of signal transducer and activator of transcription 3 (STAT3) signaling was impaired in CXCR4 CAR-T cells, which reduced the release of inflammatory factors, such as tumor necrosis factor-α, IL-6, and IL-17A. Then, the lower release of inflammatory factors suppressed SDF-1α secretion in CAFs via the nuclear factor κB (NF-κB) pathway. Therefore, the decreased secretion of SDF-1α in feedback decreased the migration of myeloid-derived suppressor cells (MDSCs) in tumor sites. Overall, our study demonstrated that CXCR4 CAR-T cells could traffic more into tumor sites and also suppress MDSC migration via the STAT3/NF-κB/SDF-1α axis to obtain better efficacy in treating CLDN18.2-positive pancreatic cancer. Our findings provide a theoretical rationale for CXCR4 CAR-T cell therapy in PDAC.

Advanced Materials and Delivery Systems for Enhancement of Chimeric Antigen Receptor Cells.

Chimeric antigen receptor (CAR) cell therapy is a great success and breakthrough in immunotherapy. However, there are still lots of barriers to its wide use in clinical, including long time consumption, high cost, and failure against solid tumors. For these challenges, researches are deplored to explore CAR cells to more appliable products in clinical. This minireview focuses on the advanced non-viral materials for CAR-T transfection ex vivo with better performance, delivery systems combined with other therapy for enhancement of CAR-T therapy in solid tumors. In addition, the targeted delivery platform for CAR cells in vivo generation as a breakthrough technology as its low cost and convenience. In the end, the prospective direction and future of CAR cell therapy are discussed.

Modulation of Radiation Doses and Chimeric Antigen Receptor T Cells: A Promising New Weapon in Solid Tumors-A Narrative Review.

Tumor behavior is determined by its interaction with the tumor microenvironment (TME). Chimeric antigen receptor (CART) cell therapy represents a new form of cellular immunotherapy (IT). Immune cells present a different sensitivity to radiation therapy (RT). RT can affect tumor cells both modifying the TME and inducing DNA damage, with different effects depending on the low and high doses delivered, and can favor the expression of CART cells. CART cells are patients' T cells genetically engineered to recognize surface structure and to eradicate cancer cells. High-dose radiation therapy (HDRT, >10-20 Gy/fractions) converts immunologically "cold" tumors into "hot" ones by inducing necrosis and massive inflammation and death. LDRT (low-dose radiation therapy, >5-10 Gy/fractions) increases the expansion of CART cells and leads to non-immunogenetic death. An innovative approach, defined as the LATTICE technique, combines a high dose in higher FDG- uptake areas and a low dose to the tumor periphery. The association of RT and immune checkpoint inhibitors increases tumor immunogenicity and immune response both in irradiated and non-irradiated sites. The aim of this narrative review is to clarify the knowledge, to date, on CART cell therapy and its possible association with radiation therapy in solid tumors.

"Off-the-Shelf" Allogeneic CAR Cell Therapy-Neglected HvG Effect.

Chimeric antigen receptor (CAR) cell therapy offers patients with hematological malignancies a new therapeutic option. Traditionally, autologous T cells are used to generate CAR designed T cells for each patient. However, this method has several drawbacks, the development of allogeneic CAR cell therapy would be a promising breakthrough that could address several of these limitations. From the clinical trials that have published data, the efficacy of allogeneic CAR cell therapy did not meet the expectations. Because of the host-versus-graft (HvG) effect, allogeneic CAR cells are eliminated by the host, resulting in short-term persistence of allogeneic CAR cells and poor efficacy. It is critical to solve the HvG effect of allogeneic CAR cells. The current commonly used methods are suppressing the host's immune system, using HLA-matched homozygous donors, reducing the expression of HLA, targeting alloreactive lymphocytes and eliminating anti-CAR activities. In this review, we will focus on the HvG effect of the "off-the-shelf" allogeneic CAR cell therapy, especially its mechanism and current methods to solve this problem and summarize relevant clinical trial data.

258 - Utilizing Biomarkers, CRP and Ferritin, to Predict the Development of Cytokine Release Syndrome in Patients Receiving Chimeric Antigen Receptor Cell Therapy

258 - Utilizing Biomarkers, CRP and Ferritin, to Predict the Development of Cytokine Release Syndrome in Patients Receiving Chimeric Antigen Receptor Cell Therapy

Vagal Nerve Activity Predicts Prognosis in Diffused Large B-Cell Lymphoma and Multiple Myeloma.

This study examined the prognostic role of vagal nerve activity in patients with relapsed/refractory diffused large B-cell lymphoma (R/R-DLBCL) treated with chimeric antigen receptor cell therapy (CAR-T) and in patients with multiple myeloma (MM) undergoing an autologous hematopoietic cell transplantation (AutoHCT). Participants included 29 patients with R/R-DLBCL and 37 patients with MM. Inclusion criteria were: (1) age over 18; (2) diagnosed with DLBCL or MM; (3) being treated with CAR-T or AutoHCT; and (4) having an ECG prior to cell transfusion. The predictor was vagal nerve activity indexed by heart rate variability (HRV) and obtained retroactively from 10 s ECGs. The main endpoint for R/R-DLBCL was overall survival (OS), and for MM the endpoint was progression-free survival (PFS). Data of 122 patients were obtained, 66 of whom were included in the study. In DLBCL, HRV significantly predicted OS independently of confounders (e.g., performance status, disease status at cell therapy), hazard ratio (HR), and 95% confidence interval (HR = 0.20; 95%CI: 0.06-0.69). The prognostic role of disease severity was moderated by HRV: among severely disease patients, 100% died with low HRV, while only 37.5% died with high HRV. In MM, HRV significantly predicted PFS (HR = 0.19; 95%CI: 0.04-0.90) independently of confounders. Vagal nerve activity independently predicts prognosis in patients with R/R-DLBCL and with MM undergoing cell therapy. High vagal activity overrides the prognostic role of disease severity. Testing the effects of vagal nerve activation on prognosis in blood cancers is recommended.

An An Overview of the Treatment of Non-Hodgkin Lymphoma with The Novel Cellular Therapies: CAR-T and Bispecific Monoclonal Antibodies

The management of non-Hodgkin lymphoma (NHL), including refractory and relapsed high grade and low-grade NHL has been significantly improved in recent years with the development of cellular therapies which harness the powerful anti-cancer effects of the immune system. These include the ground-breaking and now established technology of chimeric antigen receptor cell therapy as well as the promising new range of bispecific monoclonal antibody therapies. This article will give a summary of the currently available cellular and bi-specific antibody therapies for the treatment of NHL in licenced use and clinical trials, including an overview of their proven efficacy and characteristic side-effect profiles which distinguish them from conventional immunochemotherapy. The relative strengths and weaknesses of these comparable therapies will also be discussed together with consideration of where they may fit into the treatment sequence of NHL in the future. The article will also address the challenges of delivering these innovative technologies in different healthcare settings and how they may alter the future of therapy for patients with this form of cancer.

CAR cell design strategies in solid tumors.

In addition to chimeric antigen receptor (CAR)-αβ T-cell therapy, CAR-NK, CAR-NKT, CAR-M and CAR-γδ T-cell therapy have gradually been applied to the treatment of solid tumors. Compared to hematological tumors, solid tumors have the characteristics of strong tumor heterogeneity, limited target antigen selection, and low T-cell infiltration to build immunosuppressive tumor microenvironment. These features would present great obstacles to CAR cell therapy. This paper comprehensively analyzed the application of different CAR cells to solid tumors and summarized the design principles of different CAR cells to provide the direction for the development of CAR cell therapy in solid tumors.

Leveraging gene therapy to achieve long-term continuous or controllable expression of biotherapeutics.

T cells redirected to cancer cells either via a chimeric antigen receptor (CAR-T) or a bispecific molecule have been breakthrough technologies; however, CAR-T cells require individualized manufacturing and bispecifics generally require continuous infusions. We created an off-the-shelf, single-dose solution for achieving prolonged systemic serum levels of protein immunotherapeutics via adeno-associated virus (AAV) gene transfer. We demonstrate proof of principle in a CD19+ lymphoma xenograft model using a single intravenous dose of AAV expressing a secreted version of blinatumomab, which could serve as a universal alternative for CD19 CAR-T cell therapy. In addition, we created an inducible version using an exon skipping strategy and achieved repeated, on-demand expression up to at least 36 weeks after AAV injection. Our system could be considered for short-term and/or repeated expression of other transgenes of interest for noncancer applications.

Advances in HIV-1-specific chimeric antigen receptor cells to target the HIV-1 reservoir

Antiretroviral therapy (ART) for HIV-1 has dramatically improved outcomes for people living with HIV-1 but requires life-long adherence and can be associated with short and long-term toxicity. Numerous pre-clinical and clinical investigations are underway to develop therapies for immune control of HIV-1 in the absence of ART. The success of chimeric antigen receptor (CAR) cell therapy for hematological malignancy has renewed efforts to develop and investigate CAR cells as strategies to enhance HIV-1 immunity, enable virus control or elimination, and allow ART-free HIV-1 remission. Here, we review the improvements in anti-HIV-1 CAR cell therapy in the two decades since their initial clinical trials were conducted, describe the additional engineering required to protect CAR cells from HIV-1 infection, and preview the current landscape of CAR cell therapies advancing to HIV-1 clinical trials.

Remodeling metabolic fitness: Strategies for improving the efficacy of chimeric antigen receptor T cell therapy.

The dramatic success of adoptive transfer of engineered T cells expressing chimeric antigen receptor (CAR-T) has been achieved with effective responses in some relapsed or refractory hematologic malignancies, which is not yet met in solid tumors. The efficacy of CAR-T therapy is associated with its fate determination and their interaction with cancer cells in tumor microenvironment (TME), which is closely correlated with T cell metabolism fitness. Indeed, modulating T cell metabolism reprogramming has been proven crucial for their survival and reinvigorating antitumor immunity, and thus is considered as a promising strategy to improve the clinical performance of CAR-T cell therapy in difficult-to-treat cancers. This review briefly summarizes the T cell metabolic profiles and key metabolic challenges it faces in TME such as nutrient depletion, hypoxia, and toxic metabolites, then emphatically discusses the potential strategies to modulate metabolic properties of CAR-T cells including improving CARs construct design, optimizing manufacture process via addition of exogenous cytokines or targeting specific signaling pathway, manipulating ROS levels balance or relieving the unfavorable metabolic TME including adaptation to hypoxia and blocking inhibitory effect of toxic metabolites, eventually strengthening the anti-tumor response.