Cellular adoptive immunotherapy

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Immune cell lineage

Cellular adoptive immunotherapy is a type of immunotherapy. Immune cells such as T-cells are usually isolated from patients for expansion or engineering purposes and reinfused back into patients to fight diseases using their own immune system. A major application of cellular adoptive therapy is cancer treatment, as the immune system plays a vital role in the development and growth of cancer. [1] The primary types of cellular adoptive immunotherapies are T cell therapies. Other therapies include CAR-T therapy, CAR-NK therapy, macrophage-based immunotherapy and dendritic cell therapy.

Contents

History

Although immunotherapy with immune checkpoint blockade and targeted therapy was used to treat and improve the survival of patients with several types of cancers, such as non-small cell lung cancer, many patients still develop disease progression even after receiving these therapies. Cellular adoptive therapy is another alternative for these patients. The first studies with tumor-infiltrating lymphocytes (TILs) were performed at the Surgery Branch in the National Institutes of Health. These studies used TILs grown from different murine tumors and showed in vivo anti-tumor activity of these cells. Current cellular adoptive therapies consist of the ex-vivo expansion of TILs from resected tumors and transferred back to the patients' bodies with support of interleukin -2 (IL–2). This treatment has been shown to be effective in tumors such as metastatic melanoma. [1]

T - cell therapies

Tumor-Infiltrating Lymphocyte (TIL) Therapy

Although T- cells are powerful tools that help us defend against cancer through immune responses, errors may still occur during the process, and cancer's anti-tumour effect may vary. For example, the T- cells may not be activated and sustain the anti-tumor effect long enough, or the number of T-cells presented is insufficient. TIL therapy isolates tumor-infiltrating lymphocytes (TILs), which are naturally occurring T cells in cancer patients that have already recognised cancer cells and infiltrated into the tumor as an anti-tumor response from their own immune system after tumor resection. These isolated cells will then be cultured with interleukin-2 and tested to choose cells with high tumor recognition or selected through the "young TIL" approach. Selected cells are activated and rapidly expanded, then re-infused back into the patient. [1] [2]

Melanoma

Melanoma was the first type of tumor that provided insight into cancer immunotherapy due to its high immunogenicity. TIL therapy has been shown to be one of the most effective methods against metastatic melanoma. [3]

Other solid tumors

Apart from melanoma, TIL therapy can also be applied to other solid tumors. The presence of TILs has been considered an important factor for predicting clinical outcome and prognosis of cancer patients with different types of tumors such as Head and neck squamous cell carcinoma (A type of head and neck cancer), ovarian cancer, and renal cell carcinoma (RCC). [4] [5] [6] However, previous clinical trials of TIL therapy on patients with ovarian cancer and renal cell carcinoma have only shown mixed results and modest success respectively. [5]

Advantages

TILs in TIL therapy were exposed and stimulated by tumor antigens before isolation. These tumors often express chemokine receptors and combine with the tumor-specific T-cell receptors presented on them. This makes it easier for the TILs to target tumor cells after being re-infused. Off-target toxicity was also rarely reported in TIL therapy. [2]

A flowchart illustrating the procedure of tumor-infiltrating lymphocyte (TIL) therapy and engineered T cell receptor (TCR) therapy. Adoptive T-cell therapy.png
A flowchart illustrating the procedure of tumor-infiltrating lymphocyte (TIL) therapy and engineered T cell receptor (TCR) therapy.

Challenges

1) TIL therapy needs to overcome the heterogeneity of solid tumors, which adds difficulty to the identification of a target for all tumor cells. [2]

2) Achieving full function of T cells and tumor microenvironment (TME) with different immunosuppressive mechanisms is another primary concern. [2]

Engineered T Cell Receptor (TCR) Therapy

TCR therapy has a similar principle as TIL therapy. However, TCR therapy isolates peripheral blood T cells and engineers them to target tumor tissues. This therapy has shown to be more effective in treating solid tumors than other cellular adoptive immunotherapies such as CAR T cell therapy.

Challenges

ManufacturingThe production of TCR T-cells requires complex processes with strict monitoring. Moreover, the cost of the manufacturing process is expensive. [7]

Cost of single infusions of

axicabtagene ciloleucel: US$373,000

Tisagenlecleucel: US$475,000

T cellEfficacy of treatment highly depends on whether infused cells can persist within patients. Increasing the T - cell persistence has been a major challenge and direction for TCR therapy. [7]
Tumor microenvironmentTumor microenvironments are usually immunosuppressive. They attract immunosuppressive cells and promote cancer cell survival. Thus, making it difficult for T - cells to perform anti-tumor functions. [7]

Chimeric Antigen Receptor (CAR) T Cell Therapy

Chimeric antigen receptor T-cells (CAR-T) are predominantly used in cancer immunotherapy. T-cells are harvested from patients' bodies and infused after genetic engineering (equipped with CAR construct). And the currently developing mRNA vaccine technology may provide the possibility for in vivo CAR induction in the future.

Applications

The major application of CAR-T immunotherapy is to treat hematological malignancies, such as multiple myeloma, chronic lymphocytic leukemia, acute lymphoblastic leukemia and lymphoma. [8] Also, CAR-T-related solid tumor treatments have become increasingly promising due to protein and cell engineering improvements. [9]

Hematological malignancies

Acute lymphoblastic leukemia (ALL)

Anti-CD19 (CD19 is crucial for B cell lineage, which is overexpressed on leukemic B-cells) is the most commonly used and effective CAR in ALL treatments. Many clinical studies have reported its efficacy with satisfying complete and partial remission rates (CR and PR). [8] Besides anti-CD19, other potential candidates include anti-CD20 and immunoglobulin light chains. Further suggestions from clinical trials such as controlled CD4+ and CD8+ CAR-T could be potential strategies to investigate factors relevant to the drug efficacy, adverse effects, etc.

Other hematological malignancies

Targeting different biomarkers can treat chronic lymphocytic leukemia, lymphoma and multiple myeloma.

Solid tumors

Potential treatments for melanoma, breast cancer and sarcoma are still in the research phase. The challenges for CAR-T therapy to achieve efficacy and recent development and improvement will be discussed in the limitation and recent advances and future improvement section. [8]

Side effects

Neurological complications

Confusion, delirium and occasional seizures and cerebral edema are observed as adverse effects of anti-CD19 CAR-T, which still lack well-explained pathogenesis [3]. Furthermore, the immune effector cell-associated neurotoxicity can cause death occasionally. Some hypothesized causes such as endothelial cell activation and the increase of blood-brain barrier permeability are still under investigation. Nakinra, an anti-IL-1R antibody, has exhibited an anti-neurotoxicity effect on CAR-T treated murine model.

Cytokine release syndrome (CRS)

Hemophagocytic lymphohistiocytosis, macrophage activation syndrome, and CRS are common side effects after CAR-T treatment. [8]

Main articles: Cytokine release syndrome; chimeric antigen receptor T cell.

IgE-mediated anaphylactic reaction

CAR derived from humanized mice or human antibodies might still be recognized as a foreign antigen and be attacked by patients' immune systems, causing IgE-mediated anaphylactic responses. [8]

Advantages

CAR-T therapy exhibits distinct specificity compared to other adaptive immunotherapies and traditional cancer treatments such as chemotherapy. [8] CAR-T kill tumor cells specifically by targeting the tumor-associated antigens to keep the damage to healthy tissue at a minimum level. Additionally, these engineered T-cells can perform their function independent from HLA - major histocompatibility complex (MHC) presentation. Furthermore, CAR structure can be manipulated flexibly to target different antigens, which greatly promises the extension of its application.

Limitations

1) To achieve complete remission, manufacture of CAR-T, infusion, and efficacy of tumor-killing effect must all be successfully performed. Sometimes, it is hard to harvest sufficient T-cells from a patient, CAR-T fails to expand in vitro or in vitro, or CAR-T exhibit poor persistence. These would lead to failure to achieve durable remissions. 2) And therapy efficacy would be limited by antigen modulation related to antigen down-regulation and when infused back into patients' bodies. Hence disease relapse occurs frequently. 3) Toxicity and adverse events. 4) CAR-T treatment efficacy and safety are greatly reduced because of solid tumors' immunosuppressive microenvironment and the lack of distinct tumor antigen as the target. [10]

Recent advances and future improvements

CAR structure is continuously developing from the first generation to the fourth, improving cell expansion, efficacy, and persistence. [11]

Other therapies

CAR-NK therapy

Natural killer cells belong to the innate immune system, while they perform anti-tumor functions in a very similar mechanism to CD8+ cytotoxic T-cells. CAR-NK provides new perspectives in the cancer immunotherapy field after the advancement of CAR-T therapy.

Advantages

  1. Improved safety: mitigated cytokine release syndrome, neurotoxicity and graft-versus-host response compared to CAR-T therapy.
  2. Multiple activation mechanisms: can perform cytotoxic activity both CAR-dependently and CAR-independently.
  3. "off-the-shelf" potential. [12]

Limitations

The lack of an efficient way for gene transduction is the major limitation of CAR-NK therapy. Although retroviral vectors exhibit up to 70% efficiency with the presence of membrane-bound cytokines, it would bring problems such as insertional mutagenesis and reduced NK viability. While lentivirus transduction generally causes lower genotoxicity but with lower transfection efficiency. [12]

Dendritic cell therapy

Main article: see Cancer immunotherapy

Prospects

The final destination of cellular adoptive therapies is to create cellular products that are personalized and specific to each patient's tumor - hopefully creating products that can target different tumors in cancer patients. The future direction of cellular adoptive therapies focuses on improving anti-tumor effects of the therapies and reducing toxicity. [1]

For T - cell therapies

Increasing the reactivity of TIL towards tumor antigen through CD137 or PD-1 is a possible direction of treatment improvement. Gene editing on TILs by genetic editing tools such as Zinc finger nucleases to decrease PD-1 expression on TILs is another way to improve the efficacy of TIL therapy. [1]

Another major challenge to tackle is to reduce the 'on target, off tumor' toxicity of TCR therapy. Antigens presented only on the tumor, but not in the healthy tissue should be identified to decrease the chance of TCRs targeting healthy tissue. Side effects should also be reduced by techniques such as tumor reduction prior to therapy and dose adaptive strategies. [1]

Besides the structural development of CAR constructs, the mRNA vaccine could provide a novel platform for CAR delivery and induction in vivo. Recently, the COVID-19 mRNA vaccine was approved by the FDA, which is lipid nanoparticle loaded. If the mRNA delivery strategy is applied to cellular adoptive therapy, the manufacture of CAR immune cells could be more time-efficient and cost-effective. It means cancer patients with aggressive tumor exacerbation could be saved in time. Moreover, the currently expensive immunotherapies would be more affordable to the general public. [13]

Related Research Articles

<span class="mw-page-title-main">Natural killer cell</span> Type of cytotoxic lymphocyte

Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system. They belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cell and other intracellular pathogens acting at around 3 days after infection, and respond to tumor formation. Most immune cells detect the antigen presented on major histocompatibility complex (MHC) on infected cell surfaces, but NK cells can recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class I. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.

A cancer vaccine, or oncovaccine, is a vaccine that either treats existing cancer or prevents development of cancer. Vaccines that treat existing cancer are known as therapeutic cancer vaccines or tumor antigen vaccines. Some of the vaccines are "autologous", being prepared from samples taken from the patient, and are specific to that patient.

In biology, chimeric antigen receptors (CARs)—also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors—are receptor proteins that have been engineered to give T cells the new ability to target a specific antigen. The receptors are chimeric in that they combine both antigen-binding and T cell activating functions into a single receptor.

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology and a growing subspecialty of oncology.

<span class="mw-page-title-main">Steven Rosenberg</span> American cancer researcher

Steven A. Rosenberg is an American cancer researcher and surgeon, chief of Surgery at the National Cancer Institute in Bethesda, Maryland and a Professor of Surgery at the Uniformed Services University of Health Sciences and the George Washington University School of Medicine and Health Sciences. He pioneered the development of immunotherapy that has resulted in the first effective immunotherapies and the development of gene therapy. He is the first researcher to successfully insert foreign genes into humans.

<span class="mw-page-title-main">Ipilimumab</span> Pharmaceutical drug

Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

<span class="mw-page-title-main">Cancer immunology</span> Study of the role of the immune system in cancer

Cancer immunology (immuno-oncology) is an interdisciplinary branch of biology and a sub-discipline of immunology that is concerned with understanding the role of the immune system in the progression and development of cancer; the most well known application is cancer immunotherapy, which utilises the immune system as a treatment for cancer. Cancer immunosurveillance and immunoediting are based on protection against development of tumors in animal systems and (ii) identification of targets for immune recognition of human cancer.

<span class="mw-page-title-main">Tumor-infiltrating lymphocytes</span>

Tumor-infiltrating lymphocytes (TIL) are white blood cells that have left the bloodstream and migrated towards a tumor. They include T cells and B cells and are part of the larger category of ‘tumor-infiltrating immune cells’ which consist of both mononuclear and polymorphonuclear immune cells, in variable proportions. Their abundance varies with tumor type and stage and in some cases relates to disease prognosis.

Immunotransplant is a maneuver used to make vaccines more powerful. It refers to the process of infusing vaccine-primed T lymphocytes into lymphodepleted recipients for the purpose of enhancing the proliferation and function of those T cells and increasing immune protection induced by that vaccine.

Adoptive cell transfer (ACT) is the transfer of cells into a patient. 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.

Molecular oncology is an interdisciplinary medical specialty at the interface of medicinal chemistry and oncology that refers to the investigation of the chemistry of cancer and tumors at the molecular scale. Also the development and application of molecularly targeted therapies.

ALECSAT technology is a novel method of epigenetic cancer immunotherapy being used by the company CytoVac. It uses a patient's own immune system to target tumor cells in prostate cancer, glioblastomas, and potentially pancreatic cancer. ALECSAT research, directed by Alexei Kirken and Karine Dzhandzhugazyan, has led to several clinical trials.

<span class="mw-page-title-main">Tumor microenvironment</span> Surroundings of tumors including nearby cells and blood vessels

The tumor microenvironment (TME) is a complex ecosystem surrounding a tumor, composed of a variety of non-cancerous cells including blood vessels, immune cells, fibroblasts, signaling molecules and the extracellular matrix (ECM). Mutual interaction between cancer cells and the different components of the TME support its growth and invasion in healthy tissues which correlates with tumor resistance to current treatments and poor prognosis. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells.

The NK-92 cell line is an immortalised cell line that has the characteristics of a type of immune cell found in human blood called ’natural killer’ (NK) cells. Blood NK cells and NK-92 cells recognize and attack cancer cells as well as cells that have been infected with a virus, bacteria, or fungus. NK-92 cells were first isolated in 1992 in the laboratory of Hans Klingemann at the British Columbia Cancer Agency in Vancouver, Canada, from a patient who had a rare NK cell non-Hodgkin-lymphoma. These cells were subsequently developed into a continuously growing cell line. NK-92 cells are distinguished by their suitability for expansion to large numbers, ability to consistently kill cancer cells and testing in clinical trials. When NK-92 cells recognize a cancerous or infected cell, they secrete perforin that opens holes into the diseased cells and releases granzymes that kill the target cells. NK-92 cells are also capable of producing cytokines such as tumor necrosis factor alpha (TNF-a) and interferon gamma (IFN-y), which stimulates proliferation and activation of other immune cells.

Cytokine-induced killer cells (CIK) cells are a group of immune effector cells featuring a mixed T- and natural killer (NK) cell-like phenotype. They are generated by ex vivo incubation of human peripheral blood mononuclear cells (PBMC) or cord blood mononuclear cells with interferon-gamma (IFN-γ), anti-CD3 antibody, recombinant human interleukin (IL)-1 and recombinant human interleukin (IL)-2.

<span class="mw-page-title-main">Tumor antigens recognized by T lymphocytes</span>

T lymphocytes are cells of the immune system that attack and destroy virus-infected cells, tumor cells and cells from transplanted organs. This occurs because each T cell is endowed with a highly specific receptor that can bind to an antigen present at the surface of another cell. The T cell receptor binds to a complex formed by a surface protein named "MHC" and a small peptide of about 9 amino-acids, which is located in a groove of the MHC molecule. This peptide can originate from a protein that remains within the cell. Whereas each T cell recognizes a single antigen, collectively the T cells are endowed with a large diversity of receptors targeted at a wide variety of antigens. T cells originate in the thymus. There a process named central tolerance eliminates the T cells that have a receptor recognizing an antigen present on normal cells of the organism. This enables the T cells to eliminate cells with "foreign" or "abnormal" antigens without harming the normal cells.

Checkpoint inhibitor therapy is a form of cancer immunotherapy. The therapy targets immune checkpoints, key regulators of the immune system that when stimulated can dampen the immune response to an immunologic stimulus. Some cancers can protect themselves from attack by stimulating immune checkpoint targets. Checkpoint therapy can block inhibitory checkpoints, restoring immune system function. The first anti-cancer drug targeting an immune checkpoint was ipilimumab, a CTLA4 blocker approved in the United States in 2011.

<span class="mw-page-title-main">Michel Sadelain</span>

Michel Sadelain is an genetic engineer and cell therapist at Memorial Sloan Kettering Cancer Center, New York, New York, where he holds the Steve and Barbara Friedman Chair. He is the founding director of the Center for Cell Engineering and the head of the Gene Transfer and Gene Expression Laboratory. He is a member of the department of medicine at Memorial Hospital and of the immunology program at the Sloan Kettering Institute. He is best known for his major contributions to T cell engineering and chimeric antigen receptor (CAR) therapy, an immunotherapy based on the genetic engineering of a patient's own T cells to treat cancer.

A T memory stem cell (TSCM) is a type of long-lived memory T cell with the ability to reconstitute the full diversity of memory and effector T cell subpopulations as well as to maintain their own pool through self-renewal. TSCM represent an intermediate subset between naïve (Tn) and central memory (Tcm) T cells, expressing both naïve T cells markers, such as CD45RA+, CD45RO-, high levels of CD27, CD28, IL-7Rα (CD127), CD62L, and C-C chemokine receptor 7 (CCR7), as well as markers of memory T cells, such as CD95, CD122 (IL-2Rβ), CXCR3, LFA-1. These cells represent a small fraction of circulating T cells, approximately 2-3%. Like naïve T cells, TSCM cells are found more abundantly in lymph nodes than in the spleen or bone marrow; but in contrast to naïve T cells, TSCM cells are clonally expanded. Similarly to memory T cells, TSCM are able to rapidly proliferate and secrete pro-inflammatory cytokines in response to antigen re-exposure, but show higher proliferation potential compared with Tcm cells; their homeostatic turnover is also dependent on IL-7 and IL-15.

References

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  3. ↑ Lee, Sylvia; Margolin, Kim (2012-08-10). "Tumor-infiltrating lymphocytes in melanoma". Current Oncology Reports. 14 (5): 468–474. doi:10.1007/s11912-012-0257-5. ISSN   1523-3790. PMC   3462483 . PMID   22878966.
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  6. ↑ Almangush, Alhadi; De Keukeleire, Stijn; Rottey, Sylvie; Ferdinande, Liesbeth; Vermassen, Tijl; Leivo, Ilmo; Mäkitie, Antti A. (2022-03-18). "Tumor-Infiltrating Lymphocytes in Head and Neck Cancer: Ready for Prime Time?". Cancers. 14 (6): 1558. doi: 10.3390/cancers14061558 . ISSN   2072-6694. PMC   8946626 . PMID   35326709.
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  9. ↑ Hou, Andrew J.; Chen, Laurence C.; Chen, Yvonne Y. (2021-05-10). "Navigating CAR-T cells through the solid-tumour microenvironment". Nature Reviews Drug Discovery. 20 (7): 531–550. doi: 10.1038/s41573-021-00189-2 . ISSN   1474-1784. PMID   33972771. S2CID   234362096.
  10. ↑ Shah, Nirali N.; Fry, Terry J. (2019-03-05). "Mechanisms of resistance to CAR T cell therapy". Nature Reviews Clinical Oncology. 16 (6): 372–385. doi:10.1038/s41571-019-0184-6. ISSN   1759-4782. PMC   8214555 . PMID   30837712.
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