Vectorology - GEG Tech top picks

Multiple myeloma is the second most common hematological malignancy in the world and remains difficult to treat despite numerous therapeutic advances and drug approvals. Patients continue to experience multiple relapses and complications of the disease, affecting many areas of the body, such as the bones, kidneys and immune system. An mRNA-based CAR-T cell therapy, named Descartes-11, has been developed as a consolidative therapy in newly diagnosed high-risk multiple myeloma patients who have residual disease after the first treatment.  Descartes-11 is engineered to express CAR molecules transiently rather than permanently, which may reduce some of the short- and long-term risks associated with traditional autologous CAR-T cell therapies. This therapy is the first mRNA-based cancer treatment to enter clinical development. Phase 1 data showed no evidence of cytokine release syndrome or neurotoxicity in patients with advanced multiple myeloma. Currently, the emergence of these adverse events remains a major challenge for CAR-T cell therapies in hematological malignancies. The Phase 2 trial (NCT04436029) will enroll approximately 30 patients with newly diagnosed multiple myeloma who remain weakly positive for residual disease after initial treatment. 

Here, the scientists report the development of an alternative safeguard for chimeric antigen receptor T-cell therapies. They have incorporated a safeguard component into a conventional CAR architecture that enables tight control over CAR T-cell activity and has the potential to improve their safety profile in clinical settings. In addition, the CubiCAR architecture is compatible with multiple scFvs designed against different targets, thus bearing the potential to improve the safety of CAR T-cell immunotherapies for a broad range of patients.

The safety of lentiviral vectors is a factor in their acceptance as clinical therapies. In this issue of Molecular Therapy, Cornetta et al. (2017) screened 460 cell products for replication-competent lentivirus (RCL); none were positive. The low risk of RCL suggests that revisions to U.S. FDA testing guidelines are warranted.

The past several years have seen tremendous advances in the engineering of immune
effector cells as therapy for cancer. While chimeric antigen receptors (CARs) have
been used extensively to redirect the specificity of autologous T cells against hematological
malignancies with striking clinical results, studies of CAR-modified natural killer
(NK) cells have been largely preclinical. In this review, we focus on recent advances
in NK cell engineering, particularly on preclinical evidence suggesting that NK cells
may be as effective as T cells in recognizing and killing targets after genetic modification.

This special report discusses the concept of exploiting natural killer cell receptors as an approach that could broaden the specificity of CAR T cells and potentially enhance the efficacy of this therapy against solid tumors. New data demonstrating feasibility of this approach in humans and supporting the ongoing clinical trial are also presented.

In this review, the authors discuss the current development of CRISPR/Cas9 technologies for therapeutic applications, especially chimeric antigen receptor (CAR) T cell-based adoptive immunotherapy. Different methods used to facilitate efficient CRISPR delivery and gene editing in T cells are compared. They also address the safety concerns associated with the use of CRISPR/Cas9 gene editing and provide potential solutions and future directions of CRISPR application in the field of CAR T cell immunotherapy. 

In this trial report, the scientists demonstrated potent anti-leukemia activities of CART19s in Chinese patients with R/R ALL. Disease relapse remained the main obstacle. However, patients with a high risk of relapse after CART19s might benefit from subsequent haploidentical hematopoietic stem cell transplantation.

In this study, the authors used a lentiviral vector encoding a chimeric antigen receptor (CAR) that carries a composite CD28-CD3ζ domain for signaling and a CD19-specific scFv antibody fragment for cell binding (CAR 63.28.z). They used it to facilitate selective target-cell recognition and enhance specific cytotoxicity against B-cell acute lymphoblastic leukemia (B-ALL), we transduced CIK cells with. Their results demonstrate potent antileukemic activity of CAR-engineered CIK cells in vitro and in vivo, and suggest this strategy as a promising approach for adoptive immunotherapy of refractory pre-B-ALL.

Four early-phase studies being presented today during the 61st annual meeting of the American Society of Hematology (ASH) highlights the rapid advances being made in cellular immunotherapy for the treatment of hematological malignancies.

 Here the scientists show that independently of the starting material, operator, or device, the process consistently yielded a therapeutic dose of highly viable CAR T cells. Interestingly, the formulated product obtained with PM was comparable to that of HD with respect to cell composition, phenotype and function, even though the starting material differed significantly. Potent anti-tumor reactivity of the produced anti-CD20 CAR T cells was shown in vitro as well as in vivo. In summary, they demonstrated that the automated T cell transduction process meets the requirements for clinical manufacturing that we intend to use in two separate clinical trials for the treatment of melanoma and B cell lymphoma.

New data from the Phase 1 THINK clinical trial (NCT03018405) show that two metastatic colorectal cancer (mCRC) patients whose disease progressed following at least two prior therapies had stabilized the disease at a three-month follow-up after receiving the lowest dose level of Celyad’s NKR-2 CAR T-cell therapy.

This review focuses on CARs recognizing the B cell antigen CD19. Both retro- and lentiviral vectors are used encoding the different anti-CD19 CAR constructs comprising costimulatory molecules like CD28, CD137/4-1BB and OX40 either alone (2nd generation CARs) or in combination (3rd generation CARs). Current up-to-date published studies on anti-CD19 CAR therapy for acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL) and Non-Hodgkin lymphoma (NHL) with observed side effects are discussed and an outlook on 59 ongoing trials is given.

Cancer immunotherapy using T cells engineered ex vivo with a chimeric antigen receptor (CAR) against CD19 is currently facing major breakthroughs in the treatment of B-cell malignancies. Successful therapeutic outcome depends on long-term expression of CAR transgene in T cells, which is achieved by delivering transgene using integrating gamma retrovirus (RV) or lentivirus (LV). However, uncontrolled RV/LV integration in host cell genomes has the potential risk of causing insertional mutagenesis. In this work, the authors have designed an episomal long-term cell engineering method using non-integrating lentiviral (NILV) vector containing a scaffold/matrix attachment region (S/MAR) element. After 12 days of T-cell expansion, the scientists found that LV(CD19CAR)- and NILV-S/MAR(CD19CAR)-transduced T cells retained similar levels of CAR expression as before expansion. To meet clinical requirements, the efficacy of NILV-S/MAR (CD19CAR)-engineered T cells to control tumor growth was examined in a xenograft mouse model with Karpas 422 tumors. Mice treated with NILV-S/MAR(CD19CAR)-engineered T cells or LV(CD19CAR)-engineered T cells exhibited similarly suppressed tumor growth. The survival of tumor-bearing mice was significantly prolonged when treated with CD19 CAR T cells compared to mock T cells Taken together, the data suggest that the therapeutic efficacy of NILV-S/MAR-engineered CD19 CAR T cells is similar to that of T cells engineered with a self-inactivating integrating LV vector.

GEG Tech R&D develops also smart designs of lentiviral vectors for a safe and efficient delivery of CAR through Lenti-ONE Epi and Lenti-ONE Trans vectors.

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