Chemoimmunotherapy

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Chemoimmunotherapy is chemotherapy combined with immunotherapy. Chemotherapy uses different drugs to kill or slow the growth of cancer cells; immunotherapy uses treatments to stimulate or restore the ability of the immune system to fight cancer. A common chemoimmunotherapy regimen is CHOP combined with rituximab (CHOP-R) for B-cell non-Hodgkin lymphomas.

Contents

Introduction

Cancer therapy has evolved to strategically integrate distinct treatment modalities in order to optimize the chance of cure. Surgery and radiation therapy are used to achieve locoregional control, whereas systemic therapies (chemotherapy, endocrine therapy, molecularly targeted therapies, and adjunctive therapies (bisphosphonates)) are used to control diffuse disease (in hematologic malignancies) or disease that has spread beyond the primary site (in solid tumors). [1] Combination of different therapies in cancer has become a trend, not just between different types of therapies, also multiple drugs with complementary mechanisms. And these combinations do have a better effect on five-year survival rate and delaying tumor relapse.

Chemotherapy

In the early 1900s, the famous German chemist Paul Ehrlich set about developing drugs to treat infectious diseases. He was the one who coined the term "chemotherapy" and defined it as the use of chemicals to treat disease, he was also the first person to document the effectiveness of animal models to screen a series of chemicals for their potential activity against diseases, an accomplishment that had major ramifications for cancer drug development. During world war II, a national drug development program appeared as Cancer Chemotherapy National Service Center. [2] And good examples in curing acute childhood leukemia and advanced Hodgkin's disease encouraged people to screen more chemicals that have anti-tumor activities. Provided a diversity of anti-tumor chemicals, people started to use cocktail of different drugs and surprisingly found it would have a better outcome. At beginning, people didn't even think about cancer cell could be killed by chemicals, let alone cancer-specific therapies.

Immunotherapy

As for immunotherapy, it early mentioned by James Allison, now at the University of Texas MD Anderson Cancer Center in Houston. Allison found that CTLA-4 puts the brakes on T cells, preventing them from launching full-out immune attacks. He wondered whether blocking the blocker – the CTLA-4 molecule – would set the immune system free to destroy cancer. But at that time, people would take it as a peculiar idea, and no one supported him. But he kept studying and justified his rationale in mice. Later clinical trials reported anti-CTLA-4 antibody can increase patients with metastatic melanoma lived 4 more months, anti-PD-1 antibody also show anti-tumor effect in clinical trials. [3] Using host immune system to fight with cancer become a more and more prevalent idea in therapy. Furthermore, crosstalk between progressing tumors and the host immune system results in multiple superimposed mechanisms of additional regulation and immune escape that serve to keep the immune response to tumors shut down. A variety of immune cells that promote tumor growth and inhibit tumor-associated immune responses, including CD4+CD25+FOXP3+ regulatory T cells (Tregs), CD4+interleukin-17-producing T helper cells, myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs). Additional features of the tumor microenvironment further silence the anti-tumor immune response, including high levels of suppressive intratumoral cytokines (TGF-β, TNF, IL-10), the constitutive or induced expression of immune checkpoint molecules by the tumor cells (PD-L1, B7-H4), and various other phenotypic alterations that lead to immune escape (the loss of tumor antigens and other molecules essential for antigen processing and presentation). [4]

Crosstalk between chemotherapy and immunotherapy

Chemotherapy can promote tumor immunity in two major ways: (a) through its intended therapeutic effect of killing cancer cells by immunogenic cell death, and (b) through ancillary and largely unappreciated effects on both the malignant and normal host cells present within the tumor microenvironment. However, many standard and high-dose chemotherapy regimens can also be immunosuppressive, by either frankly inducing lymphopenia or contributing to lymphocyte dysfunction. It is clear that strategically integrating immune-based therapies with standard cancer treatment modalities, in particular chemotherapy drugs, has the potential to reengineer the overall host milieu and the local tumor microenvironment to disrupt pathways of immune tolerance and suppression.

Clinical examples

There are several good examples. The standard treatment for patients with diffuse large-B-cell lymphoma is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Rituximab, a chimeric monoclonal antibody against the CD20 B-cell antigen, has therapeutic activity in diffuse large-B-cell lymphoma5. People proved that the addition of rituximab to the CHOP regimen increases the complete-response rate and prolongs event-free and overall survival in elderly patients with diffuse large-B-cell lymphoma, without a clinically significant increase in toxicity. [5] For metastatic breast cancer that overexpresses HER2, chemoimmunotherapy also has a better effect. HER2 gene, encodes the growth factor receptor HER2, is overexpressed in 25 to 30 percent of breast cancers, increasing the aggressiveness of the tumor. Trastuzumab is a recombinant monoclonal antibody against HER2, clinical trials showed that the addition of trastuzumab to chemotherapy was associated with a longer time to disease progression, a higher rate of objective response, a longer duration of response, a lower rate of death at 1 year, longer survival, and a 20 percent reduction in the risk of death, which proves trastuzumab increases the clinical benefit of first-line chemotherapy in metastatic breast cancer that overexpresses HER2. [6]

Related Research Articles

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.

Rituximab Pharmaceutical drug

Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, idiopathic thrombocytopenic purpura, pemphigus vulgaris, myasthenia gravis and Epstein–Barr virus-positive mucocutaneous ulcers. It is given by slow injection into a vein. Biosimilars of Rituxan include Blitzima, Riabni, Ritemvia, Rituenza, Rixathon, Ruxience, and Truxima.

Cancer immunotherapy Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy is the stimulation of the immune system to treat cancer, improving on the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology and a growing subspeciality of oncology.

Targeted therapy Type of therapy

Targeted therapy or molecularly targeted therapy is one of the major modalities of medical treatment (pharmacotherapy) for cancer, others being hormonal therapy and cytotoxic chemotherapy. As a form of molecular medicine, targeted therapy blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth, rather than by simply interfering with all rapidly dividing cells. Because most agents for targeted therapy are biopharmaceuticals, the term biologic therapy is sometimes synonymous with targeted therapy when used in the context of cancer therapy. However, the modalities can be combined; antibody-drug conjugates combine biologic and cytotoxic mechanisms into one targeted therapy.

Monoclonal antibody therapy Form of immunotherapy

Monoclonal antibody therapy is a form of immunotherapy that uses monoclonal antibodies (mAbs) to bind monospecifically to certain cells or proteins. The objective is that this treatment will stimulate the patient's immune system to attack those cells. Alternatively, in radioimmunotherapy a radioactive dose localizes a target cell line, delivering lethal chemical doses. Antibodies have been used to bind to molecules involved in T-cell regulation to remove inhibitory pathways that block T-cell responses. This is known as immune checkpoint therapy.

Ipilimumab 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.

Tremelimumab

Tremelimumab is a fully human monoclonal antibody against CTLA-4. It is an immune checkpoint blocker. Previously in development by Pfizer, it is now in investigation by MedImmune, a wholly owned subsidiary of AstraZeneca. It has been undergoing human trials for the treatment of various cancers but has not attained approval for any.

Mantle cell lymphoma Medical condition

Mantle cell lymphoma (MCL) is a type of non-Hodgkin's lymphoma (NHL), comprising about 6% of NHL cases. There are only about 15,000 patients presently in the United States with mantle cell lymphoma. It is named for the mantle zone of the lymph nodes.

Nodular lymphocyte predominant Hodgkin lymphoma Medical condition

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an indolent CD20(+) form of lymphoma.

Antibody-drug conjugate Class of biopharmaceutical drugs

Antibody-drug conjugates or ADCs are a class of biopharmaceutical drugs designed as a targeted therapy for treating cancer. Unlike chemotherapy, ADCs are intended to target and kill tumor cells while sparing healthy cells. As of 2019, some 56 pharmaceutical companies were developing ADCs.

Gene expression profiling has revealed that diffuse large B-cell lymphoma (DLBCL) is composed of at least 3 different sub-groups, each having distinct oncogenic mechanisms that respond to therapies in different ways. Germinal Center B-Cell like (GCB) DLBCLs appear to arise from normal germinal center B cells, while Activated B-cell like (ABC) DLBCLs are thought to arise from postgerminal center B cells that are arrested during plasmacytic differentiation. The differences in gene expression between GCB DLBCL and ABC DLBCL are as vast as the differences between distinct types of leukemia, but these conditions have historically been grouped together and treated as the same disease.

Urelumab is a fully human IgG4 monoclonal antibody developed by Bristol-Myers Squibb for the treatment of cancer and solid tumors.

Nivolumab Cancer drug

Nivolumab, sold under the brand name Opdivo, is a medication used to treat a number of types of cancer. This includes melanoma, lung cancer, malignant pleural mesothelioma, renal cell carcinoma, Hodgkin lymphoma, head and neck cancer, urothelial carcinoma, colon cancer, esophageal squamous cell carcinoma, liver cancer, gastric cancer, and esophageal or gastroesophageal junction (GEJ) cancer. It is used by slow injection into a vein.

Abscopal effect

The abscopal effect is a hypothesis in the treatment of metastatic cancer whereby shrinkage of untreated tumors occurs concurrently with shrinkage of tumors within the scope of the localized treatment. R.H. Mole proposed the term “abscopal” in 1953 to refer to effects of ionizing radiation “at a distance from the irradiated volume but within the same organism.”

Pembrolizumab Pharmaceutical drug used in cancer treatment

Pembrolizumab, sold under the brand name Keytruda, is a humanized antibody used in cancer immunotherapy that treats melanoma, lung cancer, head and neck cancer, Hodgkin lymphoma, stomach cancer, cervical cancer, and certain types of breast cancer. It is given by slow injection into a vein.

Cryoimmunotherapy, also referred to as cryoimmunology, is an oncological treatment for various cancers that combines cryoablation of tumor with immunotherapy treatment. In-vivo cryoablation of a tumor, alone, can induce an immunostimulatory, systemic anti-tumor response, resulting in a cancer vaccine—the abscopal effect. Thus, cryoablation of tumors is a way of achieving autologous, in-vivo tumor lysate vaccine and treat metastatic disease. However, cryoablation alone may produce an insufficient immune response, depending on various factors, such as high freeze rate. Combining cryotherapy with immunotherapy enhances the immunostimulating response and has synergistic effects for cancer treatment.

Trastuzumab deruxtecan Medication

Trastuzumab deruxtecan, sold under the brand name Enhertu, is an antibody-drug conjugate consisting of the humanized monoclonal antibody trastuzumab (Herceptin) covalently linked to the topoisomerase I inhibitor deruxtecan. It is licensed for the treatment of breast cancer or gastric or gastroesophageal adenocarcinoma. Trastuzumab binds to and blocks signaling through epidermal growth factor receptor 2 (HER2/neu) on cancers that rely on it for growth. Additionally, once bound to HER2 receptors, the antibody is internalized by the cell, carrying the bound deruxtecan along with it, where it interferes with the cell's ability to make DNA structural changes and replicate its DNA during cell division, leading to DNA damage when the cell attempts to replicate itself, destroying the cell.

Primary testicular diffuse large B-cell lymphoma (PT-DLBCL), also termed testicular diffuse large B-cell lymphoma and diffuse large B-cell lymphoma of the testes, is a variant of the diffuse large B-cell lymphomas (DLBCL). DLBCL are a large and diverse group of B-cell malignancies with the great majority (-85%) being typed as diffuse large B-cell lymphoma, not otherwise specified. PT-DLBCL is a variant of DLBCL, NOS that involves one or, in uncommon cases, both testicles. Other variants and subtypes of DLBCL may involve the testes by spreading to them from their primary sites of origin in other tissues. PT-DLBCL differs from these other DLBCL in that it begins in the testes and then may spread to other sites.

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a cutaneous lymphoma skin disease that occurs mostly in elderly females. In this disease, B cells become malignant, accumulate in the dermis and subcutaneous tissue below the dermis to form red and violaceous skin nodules and tumors. These lesions typically occur on the lower extremities but in uncommon cases may develop on the skin at virtually any other site. In ~10% of cases, the disease presents with one or more skin lesions none of which are on the lower extremities; the disease in these cases is sometimes regarded as a variant of PCDLBL, LT termed primary cutaneous diffuse large B-cell lymphoma, other (PCDLBC-O). PCDLBCL, LT is a subtype of the diffuse large B-cell lymphomas (DLBCL) and has been thought of as a cutaneous counterpart to them. Like most variants and subtypes of the DLBCL, PCDLBCL, LT is an aggressive malignancy. It has a 5-year overall survival rate of 40–55%, although the PCDLBCL-O variant has a better prognosis than cases in which the legs are involved.

Passive antibody therapy, also called serum therapy, is a subtype of passive immunotherapy that administers antibodies to target and kill pathogens or cancer cells. It is designed to draw support from foreign antibodies that are donated from a person, extracted from animals, or made in the laboratory to elicit an immune response instead of relying on the innate immune system to fight disease. It has a long history from the 18th century for treating infectious diseases and is now a common cancer treatment. The mechanism of actions include: antagonistic and agonistic reaction, complement-dependent cytotoxicity (CDC), and antibody-dependent cellular cytotoxicity (ADCC).

References

  1. ↑ Emens, Leisha A. "Chemoimmunotherapy." Cancer journal (2010)
  2. ↑ DeVita, Vincent T., and Edward Chu. "A history of cancer chemotherapy." Cancer research (2008).
  3. ↑ Couzin-Frankel, Jennifer. "Cancer immunotherapy." (2013)
  4. ↑ Chen, Gang, and Leisha A. Emens. "Chemoimmunotherapy: reengineering tumor immunity." Cancer Immunology, Immunotherapy (2013).
  5. ↑ Coiffier, Bertrand, et al. "CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma." New England Journal of Medicine (2002).
  6. ↑ Slamon, Dennis J., et al. "Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2." New England Journal of Medicine (2001).
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