Adoptive cell transfer
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Adoptive cell transfer (ACT) is the transfer of cells into a patient.[1] The cells may have originated from the patient or from another individual. The cells are most commonly derived from the immune system with the goal of improving immune functionality and characteristics. In autologous cancer immunotherapy, T cells are extracted from the patient, genetically modified and cultured in vitro and returned to the same patient. Comparatively, allogeneic therapies involve cells isolated and expanded from a donor separate from the patient receiving the cells.[2]
History
In the 1960s,
Description of T cell growth factor
In 1985 IL-2 administration produced durable tumor regressions in some patients with
In 1989
Responses were often of short duration and faded days after administration. In 2002, lymphodepletion using a nonmyeloablative chemotherapy regimen administered immediately before TIL transfer increased cancer regression, as well as the persistent oligoclonal repopulation of the host with the transferred lymphocytes. In some patients, the administered antitumor cells represented up to 80% of the CD8+ T cells months after the infusion.[3]
Initially, melanoma was the only cancer that reproducibly yielded useful TIL cultures. In 2006 administration of normal circulating lymphocytes transduced with a
By 2010, doctors had begun experimental treatments for leukemia patients using CD19-targeted T cells with added DNA to stimulate cell division. As of 2015 trials had treated about 350 leukemia and lymphoma patients. Antigen CD19 appears only on
Startups including
In checkpoint therapy, antibodies bind to molecules involved in
As of 2015 the technique had expanded to treat
In 2016, researchers developed a technique that used cancer cells' RNA to produce T cells and an immune response. They encased the RNA in a negatively charged fatty membrane. In vivo, this electrical charge guided the particles towards the patient's dendritic immune cells that specify immune system targets.[7]
In 2017, researchers announced the first use of donor cells (rather than the patients' own cells) to defeat leukemia in two infants for whom other treatments had failed. The cells had four genetic modifications. Two were made using TALENs. One changed the cells so that they did not attack all the cells of another person. Another modification made tumor cells their target.[8]
Process
In melanoma, a resected melanoma specimen is digested into a single-cell suspension or divided into multiple tumor fragments. The result is individually grown in IL-2. Lymphocytes overgrow. They destroy the tumors in the sample within 2 to 3 weeks. They then produce pure cultures of lymphocytes that can be tested for reactivity against other tumors, in coculture assays. Individual cultures are then expanded in the presence of IL-2 and excess irradiated anti-CD3 antibodies. The latter targets the epsilon subunit within the human CD3 complex of the TCR. 5–6 weeks after resecting the tumor, up to 1011 lymphocytes can be obtained.[3]
Prior to infusion, a lymphodepleting preparative regimen is undergone, typically 60 mg/kg cyclophosphamide for 2 days and 25 mg/m2 fludarabine administered for 5 days. This substantially increases infused cell persistence and the incidence and duration of clinical responses. Then cells and IL-2 at 720,000 IU/kg to tolerance are infused.[3]
In early trials, preparing engineered T cells cost $75,000 to manufacture cells for each patient.[4]
In 2016 Strep-tag II sequences were introduced into synthetic CAR or natural T-cell receptors to serve as a marker for identification, rapid purification, tailoring spacer length for optimal function and selective, antibody-coated, microbead-driven, large-scale expansion. This facilitates cGMP manufacturing of pure populations of engineered T cells and enables in vivo tracking and retrieval of transferred cells for downstream research applications.[10]
Genetic engineering
Antitumor receptors genetically engineered into normal T cells can be used for therapy. T cells can be redirected by the integration of genes encoding either conventional alpha-beta TCRs or CARs. CARs (
Correlations between T cell differentiation status, cellular persistence, and treatment outcomes
Improved antitumor responses have been seen in mouse and monkey models using T cells in early differentiation stages (such as naïve or central memory cells). CD8+ T cells follow a progressive pathway of differentiation from naïve T cells into stem cell memory, central memory, effector memory, and ultimately terminally differentiated effector T cell populations.
CD4+ T cells can also promote tumor rejection. CD4+ T cells enhance CD8+ T cell function and can directly destroy tumor cells. Evidence suggests that T helper 17 cells can promote sustained antitumor immunity.[3][15][16]
Intrinsic (Intracellular) checkpoint blockade
Other modes of enhancing immuno-therapy include targeting so-called intrinsic immune checkpoint blockades. Many of these intrinsic regulators include molecules with ubiquitin ligase activity, including
Context
Neither tumor bulk nor metastasis site affect the likelihood of achieving a complete cancer regression. Of 34 complete responders in two trials, one recurred. Only one patient with complete regression received more than one treatment. Prior treatment with targeted therapy using
Stem cells
An emerging
Applications
Cancer
The adoptive transfer of autologous
Autoimmune disease
The transfer of regulatory T cells has been used to treat Type 1 diabetes and others.[25]
Trial results
Trials began in the 1990s and accelerated beginning in 2010.[3]
Cells | Year | Cancer histology | Molecular target | Patients | Number of ORs | Comments |
---|---|---|---|---|---|---|
Tumor-infiltrating lymphocytes* | 1998 | Melanoma | 20 | 55% | Original use TIL ACT | |
1994 | Melanoma | 86 | 34% | |||
2002 | Melanoma | 13 | 46% | Lymphodepletion before cell transfer | ||
2011 | Melanoma | 93 | 56% | 20% CR beyond 5 years | ||
2012 | Melanoma | 31 | 48% | |||
2012 | Melanoma | 13 | 38% | Intention to treat: 26% OR rate | ||
2013 | Melanoma | 57 | 40% | Intention to treat: 29% OR rate | ||
2014 | Cervical cancer | 9 | 22% | Probably targeting HPV antigens | ||
2014 | Bile duct | Mutated ERB2 | 1 | – | Selected to target a somatic mutation | |
In vitro sensitization | 2008 | Melanoma | NY-ESO-1 |
9 | 33% | Clones reactive against cancer-testes antigens |
2014 | Leukemia | WT-1 | 11 | – | Many treated at high risk for relapse | |
Genetically engineered with CARs | 2010 | Lymphoma | CD19 | 1 | 100% | First use of anti-CD19 CAR |
2011 | CLL | CD19 | 3 | 100% | Lentivirus used for transduction | |
2013 | ALL | CD19 | 5 | 100% | Four of five then underwent allo-HSCT | |
2014 | ALL | CD19 | 30 | 90% | CR in 90% | |
2014 | Lymphoma | 15 | 80% | Four of seven CR in DLBCL | ||
2014 | ALL | CD19 | 16 | 88% | Many moved to allo-HSCT | |
2014 | ALL | CD19 | 21 | 67% | Dose-escalation study | |
2011 | Neuroblastoma | GD2 | 11 | 27% | CR2 CARs into EBV-reactive cells | |
2016 | ALL | CD19 | 30 | 93% | J Clin Invest. 2016;126(6):2123–2138. | |
Genetically engineered with TCRs | 2011 | Synovial sarcoma | NY-ESO-1 | 6 | 67% | First report targeting nonmelanoma solid tumor |
2006 | Melanoma | MART-1 |
11 | 45% |
Solid tumors
Several ongoing clinical trials of adoptive cell therapies are ongoing in solid tumors, but challenges in the development of such therapies for this type of malignancy include the lack of surface antigens that are not found on essential normal tissues,[11] difficult-to-penetrate tumor stroma, and factors in the tumor microenvironment that impede the activity of the immune system.[32]
Safety
Toxicity
Targeting normal, nonmutated antigenic targets that are expressed on normal tissues, but overexpressed on tumors has led to severe on-target, off-tumor toxicity. Toxicity was encountered in patients who received high-avidity TCRs that recognized either the MART-1 or gp100 melanoma-melanocyte antigens, in mice when targeting melanocyte antigens, in patients with renal cancer using a CAR targeting carbonic anhydrase 9 and in patients with metastatic colorectal cancer.[3]
Toxicities can also result when previously unknown cross-reactivities are seen that target normal self-proteins expressed in vital organs. Cancer-testes antigen MAGE-A3 is not known to be expressed in any normal tissues. However, targeting an HLA-A*0201–restricted peptide in MAGE-A3 caused severe damage to gray matter in the brain, because this TCR also recognized a different but related epitope that is expressed at low levels in the brain. That CARs are potentially toxic to self-antigens was observed after infusion of CAR T cells specific for ERBB2. Two patients died when treated with an HLA-A1–restricted MAGE-A3–specific TCR whose affinity was enhanced by a site-specific mutagenesis.[3]
Cancer-testis antigens are a family of intracellular proteins that are expressed during fetal development, but with little expression in normal adult tissues. More than 100 such molecules are epigenetically up-regulated in from 10 to 80% of cancer types. However, they lack high levels of protein expression. Approximately 10% of common cancers appear to express enough protein to be of interest for antitumor T cells. Low levels of some cancer-testes antigens are expressed in normal tissues, with associated toxicities. The NYESO-1 cancer-testes antigen has been targeted via a human TCR transduced into autologous cells. ORs were seen in 5 of 11 patients with metastatic melanoma and 4 of 6 patients with highly refractory
"Suicide switches" let doctors kill engineered T cells in emergencies which threaten patient survival.[4]
Cytokine release syndrome
Cytokine release syndrome is another side effect and can be a function of therapeutic effectiveness. As the tumor is destroyed, it releases large quantities of cell signaling protein molecules. This effect killed at least seven patients.[4]
B cells
Molecules shared among tumors and nonessential normal organs represent potential ACT targets, despite the related toxicity. For example, the CD19 molecule is expressed on more than 90% of B cell malignancies and on non-plasma B cells at all differentiation stages and has been successfully used to treat patients with
Multiple other B cell antigens are being studied as targets, including
References
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- ^ a b c d e f g Regalado A (June 18, 2015). "Biotech's Coming Cancer Cure". Technology Review. Retrieved 16 October 2016.
- ^ a b "Dramatic remissions in blood cancer in immunotherapy treatment trial". www.kurzweilai.net. March 10, 2016. Retrieved 2016-03-13.[unreliable medical source?]
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- Lay summary in: Ian Johnston (June 1, 2016). "'Universal cancer vaccine' breakthrough claimed by experts". The Independent. Archived from the original on 2016-06-01.
- ^ Regalado A. "Two infants treated with universal immune cells have their cancer vanish". MIT Technology Review. Retrieved 2017-01-27.
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- Lay summary in: "Intelligent gel attacks cancer". University of Montreal Hospital Research Centre. November 19, 2015.
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External links
- Adoptive Transfer at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Adoptive Immunotherapy at the U.S. National Library of Medicine Medical Subject Headings (MeSH)