A Comprehensive Review of Recent Advancements in Cancer Immunotherapy and Generation of CAR T Cell by CRISPR-Cas9

The mechanisms involved in immune responses to cancer have been extensively studied for several decades, and considerable attention has been paid to harnessing the immune system’s therapeutic potential. Cancer immunotherapy has established itself as a promising new treatment option for a variety of cancer types. Various strategies including cancer vaccines, monoclonal antibodies (mAbs), adoptive T-cell cancer therapy and CAR T-cell therapy have gained prominence through immunotherapy. However, the full potential of cancer immunotherapy remains to be accomplished. In spite of having startling aspects, cancer immunotherapies have some difficulties including the inability to effectively target cancer antigens and the abnormalities in patients’ responses. With the advancement in technology, this system has changed the genome-based immunotherapy process in the human body including the generation of engineered T cells. Due to its high specificity, CRISPR-Cas9 has become a simple and flexible genome editing tool to target nearly any genomic locus. Recently, the CD19-mediated CAR T-cell (chimeric antigen receptor T cell) therapy has opened a new avenue for the treatment of human cancer, though low efficiency is a major drawback of this process. Thus, increasing the efficiency of the CAR T cell (engineered T cells that induce the chimeric antigen receptor) by using CRISPR-Cas9 technology could be a better weapon to fight against cancer. In this review, we have broadly focused on recent immunotherapeutic techniques against cancer and the use of CRISPR-Cas9 technology for the modification of the T cell, which can specifically recognize cancer cells and be used as immune-therapeutics against cancer.

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The Advance Cancer Immunotherapy Techniques and the Future Perspective of Modified T Cell Therapy

10.20944/preprints202105.0142.v1 ◽

2021 ◽

Author(s):

Md. Al Saber ◽

Partha Biswas ◽

Dipta Dey ◽

Md. Abu Kaium ◽

Md. Aminul Islam ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

Cancer Immunotherapy ◽

Chimeric Antigen Receptor ◽

Antigen Receptor ◽

T Cell Therapy ◽

Car T Cell ◽

Car T ◽

Engineered T Cells

The mechanisms involved in immune responses to cancer have been extensively studied for several decades and, considerable attention has been paid to harnessing the immune system's therapeutic potential. Cancer immunotherapy has established itself as a promising new treatment option for a variety of cancer types. Various strategies including cancer vaccines, monoclonal antibodies (mAbs), adoptive T-cell-cancer therapy and immune test therapy have gained prominence through immunotherapy. However, it remains to be accomplished the full potential of cancer immunotherapy. In spite of having startling aspects, the cancer immunotherapies have some difficulties including the inability to effectively targeting the cancer antigens and the abnormalities in patient response. With the advancement of technology, this system has changed the genome-based immunotherapy process in the human body including generation of engineered T cells. Due to its high specificity, CRISPR-Cas9 has become a simple and flexible genome-editing tool to target nearly any genomic locus. Recently, the CD19-mediated CAR-T cell (chimeric antigen receptor T cell) therapy has opened a new avenue for the treatment of human cancer, though low efficiency is a major drawback of this process. Thus, increasing the efficiency of the CAR-T cell (engineered T cells that induce the chimeric antigen receptor) by using CRISPR-Cas9 technology could be a better weapon to fight against the cancer. In this review, we have broadly focused on the use of CRISPR-Cas9 technology for the modification of the T-cell, which can specifically recognize cancer cells and be used as immune therapeutics against cancer. We have also demonstrated the other potential strategies for the treatment of cancer.

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The roles of T cell competition and stochastic extinction events in chimeric antigen receptor T cell therapy

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2021.0229 ◽

2021 ◽

Vol 288 (1947) ◽

Author(s):

Gregory J. Kimmel ◽

Frederick L. Locke ◽

Philipp M. Altrock

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

Chimeric Antigen Receptor ◽

Antigen Receptor ◽

T Cell Therapy ◽

Car T Cells ◽

Car T Cell ◽

Car T

Chimeric antigen receptor (CAR) T cell therapy is a remarkably effective immunotherapy that relies on in vivo expansion of engineered CAR T cells, after lymphodepletion (LD) by chemotherapy. The quantitative laws underlying this expansion and subsequent tumour eradication remain unknown. We develop a mathematical model of T cell–tumour cell interactions and demonstrate that expansion can be explained by immune reconstitution dynamics after LD and competition among T cells. CAR T cells rapidly grow and engage tumour cells but experience an emerging growth rate disadvantage compared to normal T cells. Since tumour eradication is deterministically unstable in our model, we define cure as a stochastic event, which, even when likely, can occur at variable times. However, we show that variability in timing is largely determined by patient variability. While cure events impacted by these fluctuations occur early and are narrowly distributed, progression events occur late and are more widely distributed in time. We parameterized our model using population-level CAR T cell and tumour data over time and compare our predictions with progression-free survival rates. We find that therapy could be improved by optimizing the tumour-killing rate and the CAR T cells' ability to adapt, as quantified by their carrying capacity. Our tumour extinction model can be leveraged to examine why therapy works in some patients but not others, and to better understand the interplay of deterministic and stochastic effects on outcomes. For example, our model implies that LD before a second CAR T injection is necessary.

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A comprehensive review on: Chimeric Antigen Receptor (CAR) T-cell therapy in cancer treatment

Journal of Biomedical and Pharmaceutical Research ◽

10.32553/jbpr.v9i4.776 ◽

2020 ◽

Vol 9 (4) ◽

Author(s):

Bikash Pal ◽

Bornika Chattaraj ◽

Purnima Agrawal

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

Chimeric Antigen Receptor ◽

Antigen Receptor ◽

Great Promise ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Chimeric antigen receptor T-cells or CAR T-cell therapy is a newly discovered method that has shown great promise for the global patient population to cure cancer. Chimeric antigen receptor T-cells are generally prepared by removing T-cells from the patients’ blood and modifying them using genetic engineering, to express a Chimeric Antigen Receptor on their surface. The studies done so far have shown its major effectiveness against Beta-cell malignancy, ovarian carcinoma, and lymphoblastic leukemia. The therapy can cause Cytokine Release Syndrome, neurotoxicity syndrome, tumor lysis, etc. as its major adverse event. But recent improvements in the therapy has proved that these adverse events can be effectively minimized to a great extent. The future of CAR T-cell therapy is very promising and is expected to fulfil all global regulatory requirements as well as overcome any manufacturing and toxicological obstacles and become available for a large number of populations. This review is based on the overall prospects of CAR T-cell therapy, the major toxicity related problems, and the prospect of this therapy.

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Chimeric antigen receptor signaling: Functional consequences and design implications

Science Advances ◽

10.1126/sciadv.aaz3223 ◽

2020 ◽

Vol 6 (21) ◽

pp. eaaz3223 ◽

Cited By ~ 5

Author(s):

S. E. Lindner ◽

S. M. Johnson ◽

C. E. Brown ◽

L. D. Wang

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

Chimeric Antigen Receptor ◽

Antigen Receptor ◽

Tcr Signaling ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Chimeric antigen receptor (CAR) T cell therapy has transformed the care of refractory B cell malignancies and holds tremendous promise for many aggressive tumors. Despite overwhelming scientific, clinical, and public interest in this rapidly expanding field, fundamental inquiries into CAR T cell mechanistic functioning are still in their infancy. Because CAR T cells are manufactured from donor T lymphocytes, and because CARs incorporate well-characterized T cell signaling components, it has largely been assumed that CARs signal analogously to canonical T cell receptors (TCRs). However, recent studies demonstrate that many aspects of CAR signaling are unique, distinct from endogenous TCR signaling, and potentially even distinct among various CAR constructs. Thus, rigorous and comprehensive proteomic investigations are required for rational engineering of improved CARs. Here, we review what is known about proximal CAR signaling in T cells, compare it to conventional TCR signaling, and outline unmet challenges to improving CAR T cell therapy.

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Killing Mechanisms of Chimeric Antigen Receptor (CAR) T Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20061283 ◽

2019 ◽

Vol 20 (6) ◽

pp. 1283 ◽

Cited By ~ 49

Author(s):

Mohamed-Reda Benmebarek ◽

Clara Karches ◽

Bruno Cadilha ◽

Stefanie Lesch ◽

Stefan Endres ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

Chimeric Antigen Receptor ◽

Antigen Receptor ◽

T Cell Therapy ◽

Car T Cells ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Effective adoptive T cell therapy (ACT) comprises the killing of cancer cells through the therapeutic use of transferred T cells. One of the main ACT approaches is chimeric antigen receptor (CAR) T cell therapy. CAR T cells mediate MHC-unrestricted tumor cell killing by enabling T cells to bind target cell surface antigens through a single-chain variable fragment (scFv) recognition domain. Upon engagement, CAR T cells form a non-classical immune synapse (IS), required for their effector function. These cells then mediate their anti-tumoral effects through the perforin and granzyme axis, the Fas and Fas ligand axis, as well as the release of cytokines to sensitize the tumor stroma. Their persistence in the host and functional outputs are tightly dependent on the receptor’s individual components—scFv, spacer domain, and costimulatory domains—and how said component functions converge to augment CAR T cell performance. In this review, we bring forth the successes and limitations of CAR T cell therapy. We delve further into the current understanding of how CAR T cells are designed to function, survive, and ultimately mediate their anti-tumoral effects.

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Interventions and Outcomes of Adult Patients with B-ALL Progressing After CD19 Chimeric Antigen Receptor T Cell Therapy

Blood ◽

10.1182/blood.2020009515 ◽

2021 ◽

Author(s):

Kitsada Wudhikarn ◽

Jessica R Flynn ◽

Isabelle Rivière ◽

Mithat Gonen ◽

Xiuyan Wang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

Chimeric Antigen Receptor ◽

Antigen Receptor ◽

Adult Patients ◽

T Cell Therapy ◽

Car T Cells ◽

Car T Cell ◽

Car T

CD19-targeted chimeric antigen receptor (CAR) T cell therapy has become a breakthrough treatment for patients with relapsed/refractory B acute lymphoblastic leukemia (B-ALL). However, despite the high initial response rate, the majority of adult patients with B-ALL progress after CD19 CAR T therapy. Data on the natural history, management, and outcome of adult B-ALL progressing after CD19 CAR T cells have not been described in detail. Herein, we report comprehensive data of 38 adult B-ALL patients who progressed after CD19 CAR T therapy at our institution. The median time to progression after CAR T therapy was 5.5 months. Median survival after post-CAR T progression was 7.4 months. A high disease burden at the time of CAR T cell infusion was significantly associated with risk of post-CAR T progression. Thirty patients (79%) received salvage treatment for post-CAR T disease progression and 13 patients (43%) achieved complete remission (CR), but remission duration was short. Notably, 7 of 12 patients (58.3%) achieved CR after blinatumomab and/or inotuzumab administered after post-CAR T failure. Multivariate analysis demonstrated longer remission duration from CAR T cells was associated with superior survival after progression following CAR T therapy. In conclusion, overall prognosis of adult B-ALL patients progressing after CD19 CAR T cells was poor though a subset of patients achieved sustained remissions to salvage treatments including blinatumomab, inotuzumab and re-infusion of CAR T cells. Novel therapeutic strategies are needed to reduce risk of progression after CAR T therapy and improve outcomes of these patients.

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Chimeric antigen receptor (CAR) immunotherapy: basic principles, current advances, and future prospects in neuro-oncology

Immunologic Research ◽

10.1007/s12026-021-09236-x ◽

2021 ◽

Author(s):

Hyeon Joo Yoo ◽

Biyan Nathanael Harapan

Keyword(s):

T Cell ◽

Cell Therapy ◽

Cancer Immunotherapy ◽

Solid Tumors ◽

Chimeric Antigen Receptor ◽

Antigen Receptor ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

AbstractWith recent advances, chimeric antigen receptor (CAR) immunotherapy has become a promising modality for patients with refractory cancer diseases. The successful results of CAR T cell therapy in relapsed and refractory B-cell malignancies shifted the paradigm of cancer immunotherapy by awakening the scientific, clinical, and commercial interest in translating this technology for the treatment of solid cancers. This review elaborates on fundamental principles of CAR T cell therapy (development of CAR construct, challenges of CAR T cell therapy) and its application on solid tumors as well as CAR T cell therapy potential in the field of neuro-oncology. Glioblastoma (GBM) is identified as one of the most challenging solid tumors with a permissive immunological milieu and dismal prognosis. Standard multimodal treatment using maximal safe resection, radiochemotherapy, and maintenance chemotherapy extends the overall survival beyond a year. Recurrence is, however, inevitable. GBM holds several unique features including its vast intratumoral heterogeneity, immunosuppressive environment, and a partially permissive anatomic blood–brain barrier, which offers a unique opportunity to investigate new treatment approaches. Tremendous efforts have been made in recent years to investigate novel CAR targets and target combinations with standard modalities for solid tumors and GBM to improve treatment efficacy. In this review, we outline the history of CAR immunotherapy development, relevant CAR target antigens validated with CAR T cells as well as preclinical approaches in combination with adjunct approaches via checkpoint inhibition, bispecific antibodies, and second-line systemic therapies that enhance anticancer efficacy of the CAR-based cancer immunotherapy.

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Toxicities of chimeric antigen receptor T cells: recognition and management

Blood ◽

10.1182/blood-2016-04-703751 ◽

2016 ◽

Vol 127 (26) ◽

pp. 3321-3330 ◽

Cited By ~ 485

Author(s):

Jennifer N. Brudno ◽

James N. Kochenderfer

Keyword(s):

T Cells ◽

T Cell ◽

Cell Therapy ◽

Chimeric Antigen Receptor ◽

Antigen Receptor ◽

T Cell Therapy ◽

Car T Cells ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T

Abstract Chimeric antigen receptor (CAR) T cells can produce durable remissions in hematologic malignancies that are not responsive to standard therapies. Yet the use of CAR T cells is limited by potentially severe toxicities. Early case reports of unexpected organ damage and deaths following CAR T-cell therapy first highlighted the possible dangers of this new treatment. CAR T cells can potentially damage normal tissues by specifically targeting a tumor-associated antigen that is also expressed on those tissues. Cytokine release syndrome (CRS), a systemic inflammatory response caused by cytokines released by infused CAR T cells can lead to widespread reversible organ dysfunction. CRS is the most common type of toxicity caused by CAR T cells. Neurologic toxicity due to CAR T cells might in some cases have a different pathophysiology than CRS and requires different management. Aggressive supportive care is necessary for all patients experiencing CAR T-cell toxicities, with early intervention for hypotension and treatment of concurrent infections being essential. Interleukin-6 receptor blockade with tocilizumab remains the mainstay pharmacologic therapy for CRS, though indications for administration vary among centers. Corticosteroids should be reserved for neurologic toxicities and CRS not responsive to tocilizumab. Pharmacologic management is complicated by the risk of immunosuppressive therapy abrogating the antimalignancy activity of the CAR T cells. This review describes the toxicities caused by CAR T cells and reviews the published approaches used to manage toxicities. We present guidelines for treating patients experiencing CRS and other adverse events following CAR T-cell therapy.

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Chimeric antigen receptor T cells immunotherapy: challenges and opportunities in hematological malignancies

Immunotherapy ◽

10.2217/imt-2020-0181 ◽

2020 ◽

Vol 12 (18) ◽

pp. 1341-1357

Author(s):

Nashwa El-Khazragy ◽

Sherief Ghozy ◽

Passant Emad ◽

Mariam Mourad ◽

Diaaeldeen Razza ◽

...

Keyword(s):

T Cell ◽

Cell Therapy ◽

Chimeric Antigen Receptor ◽

Hematological Malignancies ◽

Antigen Receptor ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Challenges And Opportunities

Taking advantage of the cellular immune system is the mainstay of the adoptive cell therapy, to induce recognition and destruction of cancer cells. The impressive demonstration of this principle is chimeric antigen receptor-modified T (CAR-T)-cell therapy, which had a major impact on treating relapsed and refractory hematological malignancies. Despite the great results of the CAR-T-cell therapy, many tumors are still able to avoid immune detection and further elimination, as well as the possible associated adverse events. Herein, we highlighted the recent advances in CAR-T-cell therapy, discussing their applications beneficial functions and side effects in hematological malignancies, illustrating the underlying challenges and opportunities. Furthermore, we provide an overview to overcome different obstacles using potential manufacture and treatment strategies.

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