Adoptive T cell transfer for cancer and chronic infection is an emerging field that shows promise in recent trials. Synthetic-biology-based engineering of T lymphocytes to express high-affinity ...antigen receptors can overcome immune tolerance, which has been a major limitation of immunotherapy-based strategies. Advances in cell engineering and culture approaches to enable efficient gene transfer and ex vivo cell expansion have facilitated broader evaluation of this technology, moving adoptive transfer from a “boutique” application to the cusp of a mainstream technology. The major challenge currently facing the field is to increase the specificity of engineered T cells for tumors, because targeting shared antigens has the potential to lead to on-target off-tumor toxicities, as observed in recent trials. As the field of adoptive transfer technology matures, the major engineering challenge is the development of automated cell culture systems, so that the approach can extend beyond specialized academic centers and become widely available.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Lessons from arthritis and cell therapy in cancer patients point to therapy for severe disease
In December 2019, a new strain of coronavirus, severe acute respiratory syndrome–coronavirus 2 ...(SARS-CoV-2), was recognized to have emerged in Wuhan, China. Along with SARS-CoV and Middle East respiratory syndrome–coronavirus (MERS-CoV), SARS-CoV-2 is the third coronavirus to cause severe respiratory illness in humans, called coronavirus disease 2019 (COVID-19). This was recognized as a pandemic by the World Health Organization (WHO) in March 2020 and has had considerable global economic and health impacts. Although the situation is rapidly evolving, severe disease manifested by fever and pneumonia, leading to acute respiratory distress syndrome (ARDS), has been described in up to 20% of COVID-19 cases. This is reminiscent of cytokine release syndrome (CRS)–induced ARDS and secondary hemophagocytic lymphohistiocytosis (sHLH) observed in patients with SARS-CoV and MERS-CoV as well as in leukemia patients receiving engineered T cell therapy. Given this experience, urgently needed therapeutics based on suppressing CRS, such as tocilizumab, have entered clinical trials to treat COVID-19.
Chimeric Antigen Receptor Therapy June, Carl H; Sadelain, Michel
New England journal of medicine/The New England journal of medicine,
07/2018, Volume:
379, Issue:
1
Journal Article
Peer reviewed
Open access
This review addresses T-cell engineering and synthetic immunity, with a focus on producing durable remissions in patients with treatment-refractory tumors. Toxic effects of chimeric antigen receptor ...therapies include cytokine release syndrome and neurologic dysfunction.
Emerging Cellular Therapies for Cancer Guedan, Sonia; Ruella, Marco; June, Carl H
Annual review of immunology,
04/2019, Volume:
37, Issue:
1
Journal Article
Peer reviewed
Open access
Genetically engineered T cells are powerful new medicines, offering hope for curative responses in patients with cancer. Chimeric antigen receptor (CAR) T cells were recently approved by the US Food ...and Drug Administration and are poised to enter the practice of medicine for leukemia and lymphoma, demonstrating that engineered immune cells can serve as a powerful new class of cancer therapeutics. The emergence of synthetic biology approaches for cellular engineering provides a broadly expanded set of tools for programming immune cells for enhanced function. Advances in T cell engineering, genetic editing, the selection of optimal lymphocytes, and cell manufacturing have the potential to broaden T cell-based therapies and foster new applications beyond oncology, in infectious diseases, organ transplantation, and autoimmunity.
Cytokine Storm Fajgenbaum, David C; June, Carl H
The New England journal of medicine,
12/2020, Volume:
383, Issue:
23
Journal Article
Peer reviewed
Open access
Cytokine storm, a life-threatening disorder involving cytokine elevations and immune-cell hyperactivation, has various causes and is characterized by constitutional symptoms, systemic inflammation, ...and multiorgan dysfunction. Selective interventions can ameliorate the illness.
Chimeric antigen receptor （CAR） gene-engineered T cell therapy holds the potential to make a meaningful differ- ence in the lives of patients with terminal cancers. For decades, cancer therapy was ...based on biophysical parameters, with surgical resection to debulk, followed by radiation and chemotherapy to target the rapidly growing tumor cells, while mostly sparing quiescent normal tissues. One breakthrough occurred with allogeneic bone-marrow transplant for patients with leukemia, which provided a sometimes curative therapy. The field of adoptive cell therapy for sol- id tumors was established with the discovery that tumor-infiltrating lymphocytes could be expanded and used to treat and even cure patients with metastatic melanoma. Tumor-specific T-cell receptors （TCRs） were identified and engineered into patient peripheral blood lymphocytes, which were also found to treat tumors. However, these were limited by patient HLA-restriction. Close behind came generation of CAR, combining the exquisite recognition of an antibody with the effector function of a T cell. The advent of CD19-targeted CARs for treating patients with multiple forms of advanced B-cell malignancies met with great success, with up to 95% response rates. Applying CAR treat- ment to solid tumors, however, has just begun, but already certain factors have been made clear： the tumor target is of utmost importance for clinicians to do no harm; and solid tumors respond differently to CAR therapy compared with hematologic ones. Here we review the state of clinical gene-engineered T cell immunotherapy, its successes, chal- lenges, and future.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The emergence of immuno-oncology as the first broadly successful strategy for metastatic cancer will require clinicians to integrate this new pillar of medicine with chemotherapy, radiation, and ...targeted small-molecule compounds. Of equal importance is gaining an understanding of the limitations and toxicities of immunotherapy. Immunotherapy was initially perceived to be a relatively less toxic approach to cancer treatment than other available therapies-and surely it is, when compared to those. However, as the use of immunotherapy becomes more common, especially as first- and second-line treatments, immunotoxicity and autoimmunity are emerging as the Achilles' heel of immunotherapy. In this Perspective, we discuss evidence that the occurrence of immunotoxicity bodes well for the patient, and describe mechanisms that might be related to the induction of autoimmunity. We then explore approaches to limit immunotoxicity, and discuss the future directions of research and reporting that are needed to diminish it.
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IJS, NUK, SBMB, UL, UM, UPUK
Summary
On July 1, 2014, the United States Food and Drug Administration granted ‘breakthrough therapy’ designation to CTL019, the anti‐CD19 chimeric antigen receptor T‐cell therapy developed at the ...University of Pennsylvania. This is the first personalized cellular therapy for cancer to be so designated and occurred 25 years after the first publication describing genetic redirection of T cells to a surface antigen of choice. The peer‐reviewed literature currently contains the outcomes of more than 100 patients treated on clinical trials of anti‐CD19 redirected T cells, and preliminary results on many more patients have been presented. At last count almost 30 clinical trials targeting CD19 were actively recruiting patients in North America, Europe, and Asia. Patients with high‐risk B‐cell malignancies therefore represent the first beneficiaries of an exciting and potent new treatment modality that harnesses the power of the immune system as never before. A handful of trials are targeting non‐CD19 hematological and solid malignancies and represent the vanguard of enormous preclinical efforts to develop CAR T‐cell therapy beyond B‐cell malignancies. In this review, we explain the concept of chimeric antigen receptor gene‐modified T cells, describe the extant results in hematologic malignancies, and share our outlook on where this modality is likely to head in the near future.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Chimeric antigen receptor (CAR) T cells have proven that engineered immune cells can serve as a powerful new class of cancer therapeutics. Clinical experience has helped to define the major ...challenges that must be met to make engineered T cells a reliable, safe, and effective platform that can be deployed against a broad range of tumors. The emergence of synthetic biology approaches for cellular engineering is providing us with a broadly expanded set of tools for programming immune cells. We discuss how these tools could be used to design the next generation of smart T cell precision therapeutics.
The emergence of synthetic biology approaches for cellular engineering is providing us with a broadly expanded set of tools that can be used to design the next generation of smart T cell precision therapeutics for cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Delivery technologies for cancer immunotherapy Riley, Rachel S; June, Carl H; Langer, Robert ...
Nature reviews. Drug discover/Nature reviews. Drug discovery,
03/2019, Volume:
18, Issue:
3
Journal Article
Peer reviewed
Open access
Immunotherapy has become a powerful clinical strategy for treating cancer. The number of immunotherapy drug approvals has been increasing, with numerous treatments in clinical and preclinical ...development. However, a key challenge in the broad implementation of immunotherapies for cancer remains the controlled modulation of the immune system, as these therapeutics have serious adverse effects including autoimmunity and nonspecific inflammation. Understanding how to increase the response rates to various classes of immunotherapy is key to improving efficacy and controlling these adverse effects. Advanced biomaterials and drug delivery systems, such as nanoparticles and the use of T cells to deliver therapies, could effectively harness immunotherapies and improve their potency while reducing toxic side effects. Here, we discuss these research advances, as well as the opportunities and challenges for integrating delivery technologies into cancer immunotherapy, and we critically analyse the outlook for these emerging areas.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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