Personalized immunotherapy for the treatment of non-Hodgkin's lymphoma: a promising approach

The efficacy of immunotherapeutic strategies for the treatment of lymphoid malignancies has been demonstrated in recent years. In patients with B-cell lymphomas, particularly indolent lymphoma, the use of passive immunotherapy, such as the anti-CD20 monoclonal antibody rituximab, has made an impressive impact on patient outcome. Personalized immunotherapy, a method that triggers the immune system to mount a response against tumor cells, has shown promising results in early clinical trials in hematologic malignancies. This therapeutic modality appears safe, with the most common adverse events being transient, local reactions at the site of injection. Furthermore, personalized immunotherapy has the potential to generate immunologic memory, which could provide prolonged remission. Currently, 3 large phase III studies are evaluating the efficacy and safety of personalized immunotherapy in patients with follicular lymphoma. It is hoped that the results of these studies will lead to the incorporation of this promising approach into the standard treatment of patients with lymphoma.     

Adaptive immunity in hepatocellular carcinoma: prognostic and therapeutic implications

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world and has a poor prognosis. Host immunity can either protect or promote tumor growth by the predominance and activation of certain subsets of immune cells. It has been established that antigens such as AFP, MAGE, glypican 3 and NY-ESO, which are highly expressed in HCC, are potential targets for T-cell responses. Several studies have come to the conclusion that cytotoxic T-cell infiltration of the tumors is indicative of a better survival, whereas the predominance of suppressor cells is associated with a worse outcome and lower survival rates. Finally, certain therapeutic strategies, including radiofrequency ablation and chemoembolization, can enhance the release and exposure of tumor antigens, which might help to overcome the immune tolerance towards the tumor. Therefore, such immune-stimulating therapeutic interventions in combination with immunotherapy strategies represent a promising future approach for HCC treatment.     

The landscape of new drugs in extranodal NK/T-cell lymphoma

To date, much progress has been made in early-stage extranodal NK/T-cell lymphoma (ENKTCL), and risk-adapted therapy with radiotherapy (RT) alone for the low-risk group and RT combined with asparaginase-based chemotherapy (CT) for the high-risk group yields favorable outcomes. However, optimal treatment strategies have not been defined yet for advanced-stage ENKTCL. Historically, ENKTCL responded poorly to conventional anthracycline-based chemotherapy probably because of inherent multidrug resistance (MDR). The fact that ENKTCL cells lack asparagine synthetase (ASNS) activity warranted the use of L-asparaginase or pegaspargase as frontline chemotherapies. Even though, due to high mortality of the disease, approximately 50% patients failing the frontline therapy arrived at dismal clinical outcomes with a median progression-free survival (PFS) less than 8 months. As distinctive molecular and biological subgroups are increasingly discovered within the disease entity of ENKTCL, novel targeted therapies and immunotherapy are of the urgent need for those heterogeneous subgroups. In this review, we sought to summarize the preclinical and clinical results of 6 categories of promising targeted therapy and immunotherapy for the treatment of ENKTCL, including monoclonal antibodies, immune checkpoint inhibitors, small-molecular inhibitors, epigenetic therapy, immunomodulatory drugs, and adoptive T-cell therapy, and these might change the landscape of treatment for ENKTCL in the near future.     

Towards defining specific antigens for cutaneous lymphomas

Cutaneous lymphomas (CLs) are a heterogeneous group of malignancies of T-cell (cutaneous T-cell lymphoma, CTCL) or B-cell (cutaneous B-cell lymphoma, CBCL) origin with primary manifestation in the skin. CLs are difficult to treat in their advanced stages, especially as there is no curative treatment available. Immunological therapies might be a promising alternative, but the prerequisite for such strategies is the knowledge of tumor-specific antigens. This paper is reviewing the methods used today for identifying such antigens with special respect to CLs. The most successful strategies for the discovery of new tumor antigens include the cytotoxic T-cell approach using either genetic or biochemical tools, or synthetic peptide libraries leading to so-called mimotopes. A second strategy utilizes antibodies for screening recombinant libraries: either monoclonal antibodies generated against tumor cells or the so-called SEREX approach using antibodies of the patient's serum. Especially the antibody-based strategies led to several new antigens expressed in CTCL. Finally, already known tumor antigens have been evaluated as possible targets for CLs. A growing list of tumor antigens can be summarized for CLs, especially CTCL, which include cTAGE-1, SCP-1, GBP-TA, several mimotopes, SC5, LAGE-1, and NY-ESO-1, as well as the GAGE and MAGE-A groups. Perspectives on basis of the present knowledge are discussed.     

Cutaneous T-cell lymphomas: Focusing on novel agents in relapsed and refractory disease

Patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL) display a dismal prognosis and their therapy represents an unmet medical need, as the best treatment strategy is yet to be determined. Exciting data on novel targeted agents are now emerging from recently concluded and ongoing clinical trials in patients with relapsed and refractory CTCL. Three FDA approved compounds are used as single agents including the oral retinoid bexarotene and histone deacetylase inhibitors romidepsin and vorinostat. Brentuximab vedotin, an anti-CD30 drug-conjugated monoclonal antibody, has received from European Commission the orphan designation but has not been approved by EMA yet. Several other molecules have demonstrated their activity in the same context and combination strategies are being explored. Participation in a well designed clinical trial is encouraged, as the introduction of novel agents will continue to expand the therapeutics options available in the management of CTCL.     

Critical care management of chimeric antigen receptor T-cell therapy recipients

Chimeric antigen receptor (CAR) T-cell therapy is a promising immunotherapeutic treatment concept that is changing the treatment approach to hematologic malignancies. The development of CAR T-cell therapy represents a prime example for the successful bench-to-bedside translation of advances in immunology and cellular therapy into clinical practice. The currently available CAR T-cell products have shown high response rates and long-term remissions in patients with relapsed/refractory acute lymphoblastic leukemia and relapsed/refractory lymphoma. However, CAR T-cell therapy can induce severe life-threatening toxicities such as cytokine release syndrome, neurotoxicity, or infection, which require rapid and aggressive medical treatment in the intensive care unit setting. In this review, the authors provide an overview of the state-of-the-art in the clinical management of severe life-threatening events in CAR T-cell recipients. Furthermore, key challenges that have to be overcome to maximize the safety of CAR T cells are discussed.     

CD30＋T细胞淋巴瘤的治疗现状及展望：第19届欧洲血液学会年会报道

外周T细胞淋巴瘤中以CD30＋T细胞淋巴瘤居多,目前尚无统一的标准治疗方案.常用的策略是多种药物组成的剂量增强的化疗方案,联合造血干细胞移植进行巩固.近年,多个包含新药附加方案的临床试验,如依托泊苷、阿仑单抗、地尼白介素-毒素连接物、硼替佐米、罗米地辛、来那度胺、brentuximab vedotin等,结果令人鼓舞.针对难治性/复发性CD30＋T细胞淋巴瘤,获批的药物有普拉曲沙、罗米地辛、brentuximab vedotin（对间变大细胞淋巴瘤）、belinostat等,其中以brentuximab vedotin前景最为乐观.     

嵌合抗原受体T细胞治疗胰腺癌的现状及未来策略

嵌合抗原受体（chimeric antigen receptor,CAR）T细胞作为肿瘤免疫治疗领域的新兴疗法在B细胞系血液系统肿瘤中已经获得了较为满意的疗效,因此,CAR-T细胞疗法也被列为包括胰腺癌在内的实体肿瘤治疗的新探索方向。尽管实体瘤本身的异质性、微环境的复杂性导致单纯的CAR-T细胞治疗效果不尽如人意,但随着新技术的开发,CAR结构的优化,各种免疫佐剂的联合应用使CAR-T细胞疗法值得进一步研究。该文就CAR-T细胞疗法的特点、治疗胰腺癌的现状及未来方向进行概述。     

Biological therapy of colorectal cancer

In this review, the immunogenicity of colorectal cancer (CRC) and the results of clinical and recent preclinical studies are discussed. Evidence for immune reactivity has been found in several preclinical models and the prognostic value of some of these immune responses have been reported. The possible mechanisms are discussed. Treatment with monoclonal antibodies is still experimental; as previously described benefit of treatment with monoclonal antibodies could not be confirmed. Labelled monoclonal antibody therapy has produced mixed results and also need further investigation. Several antigens are used in active specific immunotherapy (ASI). Its targets and modifications are discussed, as are their use in clinical studies. Although some of the results are promising, the results still have to be confirmed in larger studies. Since there is sufficient evidence for immune reactivity in CRC, further research on immunotherapeutic strategies is justified and will be focused on the development of humanised antibodies, the search for other relevant T-cell epitopes and ways to induce a more effective T cell response.     

Anti-CD30 Antibodies for Hodgkin Lymphoma

Treatment of refractory or relapsed classical Hodgkin lymphoma (HL) remains challenging, but targeted immunotherapy has recently emerged as a potential treatment option for these patients. Although first-generation monoclonal anti-CD30 antibodies proved disappointing, current efforts to modify anti-CD30 antibodies to improve binding of effector cells and enhance activity appears more promising, as does the development of novel antibody-drug conjugates (ADCs). ADCs offer the potential to deliver potent therapies with minimal toxicity. One highly active ADC, brentuximab vedotin (SGN-35), combines an anti-CD30 monoclonal antibody and the antitubulin agent monomethyl auristatin E. Initial phase 1 studies of brentuximab vedotin showed a 52% overall response rate in relapsed HL, with minimal toxicity. This article highlights the development of anti-CD30 antibodies and ADCs for relapsed or refractory classical HL.     

Monoclonal antibody for cancer treatment

Antibodies have for many decades been viewed as ideal molecules for cancer therapy. Although promising from the start, it has taken much of more than two decades to reach the level of clinical application. Genetic engineering of antibodies; that is novel technologies for chimeric or humanizing monoclonal antibodies, has greatly advanced their utility in molecular targeting therapies, and in the past four years some therapeutic monoclonal antibodies for hematologic malignancies and solid tumors, such as Rituximab for B-cell lymphoma and Trastuzumab for metastatic breast cancer, have provided sufficient efficacy and safety to support regulatory approval from the U.S. Food and Drug Administration. They were subsequently approved by the Japanese Ministry of Health, Labour and Welfare in 2001. Many molecular biological and immunological studies have revealed the targeting properties of the host immune system and the biological mechanism of cancer cells for a more specific anticancer effect. Many clinical trials of monoclonal antibodies as a single agent, or in combination protocol with current standard chemotherapy or immunoconjugates have shown promise in the treatment of specific diseases. Furthermore, novel antibody designs and improved understanding of the mode of action of current antibodies lend great hope to the future of this therapeutic approach. The accumulating results from many basic, clinical and translational studies may lead to more individualized therapeutic strategies using these agent directed at specific genetic and immunologic targets.     

Malignant large cell lymphoma of B-cell type with multilobated nuclei. Report of a case and review of the literature

Malignant lymphomas with multilobated nuclei are rare, recently recognized neoplasms of the immune system initially thought to be of T-cell type. Reported is a case of large cell lymphoma with multilobated nuclei in which immunologic marker studies demonstrated that the neoplastic cells had characteristics of B-lymphocytes. The neoplastic cells possessed surface and cytoplasmic immunoglobulin of the IgG, lambda type, and stained diffusely with monoclonal antibodies to B1, Leu-10 and OKIaI antigens and focally with anti-B2. The lymphoma cells did not react with monoclonal antibodies directed against T-cells and monocytes/granulocytes. As documented here with multiple monoclonal antibody lymphocyte markers, the multilobated lymphoma can have a B-cell phenotype as well as the cell phenotype described previously. Thus, even the unique finding of multilobated nuclear morphologic features is unreliable in predicting the lymphocyte lineage.     

Brentuximab vedotin, a highly active ADC as a new therapeutic option for CD30+ lymphomas

Hodgkin lymphoma (HL) and systemic anaplastic large-cell lymphoma (sALCL) are lymphoproliferative types of cancer. The chemotherapy regimens of HL such as ABVD (doxorubicin, bleomycin, vinblastine, decarbazine) and BEACOPP (bleomycin, etoposide, doxorubicin, cyclophospamide, vincristine, procarbazine, prednisone) have made the most curable malignancies. Unfortunately, 15–30?% of these patients will relapse again and treatment options become limited, so we need to develop new therapeutic approaches. ALCL has unique molecular and immunohistochemical features that make it an ideal model for developing targeted therapies. Antibody-drug conjugates (ADCs), consist of an antibody, a cytotoxic agent, a stable linker and allow delivery of high doses of cytotoxic drugs to cancer cells while sparing normal tissues exposure to high systemic concentration of the cytotoxic agent. Brentuximab vedotin is an anti-CD30 monoclonal antibody conjugate with a potent microtubule inhibitor monomethyl auristatin E. In August 2011, the United States Food and Drug Administration (FDA) approved brentuximab vedotin to treat HL after failure of autologous stem cell transplantation or at least two combination chemotheraphy regimens and for sALCL after failure of at least one prior multidrug chemotherapy regimen. With this approval, brentuximab vedotin is a promising ADC directed against the CD30 antigen.     

Therapy of chronic lymphocytic leukemia and cutaneous T-cell lymphoma with T101 monoclonal antibody

The findings accompanying the administration of 50 intravenous courses of monoclonal antibody to human T-cell (T101) in eight patients, four with chronic lymphocytic leukemia and four with cutaneous T-cell lymphoma are reported. Infusion rates of 0.7 to 1 mg/min were associated with unacceptable toxicity in the presence of circulating target cells, but slower rates were well-tolerated. Immunofluorescence techniques confirmed that circulating cells did bind the antibody in vivo and were subsequently removed from the circulation. Modulation of the antigen on target cells in the bone marrow and skin has important implications for the schedule of administration of such antibodies, and points out the possible limitation of effector cell-mediated cytotoxicity at the tissue level. Production of anti-mouse antibodies resulted in neutralization of therapy in two patients with cutaneous T-cell lymphoma, and suggests that whether such an anti-mouse response is produced may be secondary to the underlying immune status of the patient or the amount of mouse protein to which immunocompetent cells are exposed. The relative specificity and efficacy of monoclonal antibody therapy is encouraging, but the limited clinical benefit and problems of modulation and anti-mouse antibody production underscore the need for continued research into passive therapy and suggest that cytotoxic conjugates may be of more clinical value.     

Immunotherapy for lung cancer: Focusing on chimeric antigen receptor (CAR)-T cell therapy

Besides traditional treatment strategies, including surgery, radiotherapy, and chemotherapy for lung cancer as the leading cause of cancer incidence and death, immunotherapy has also emerged as a new treatment strategy. The goal of immunotherapy is to stimulate the immune system responses against cancer, using various approaches such as therapeutic vaccines, monoclonal antibodies, immune checkpoint inhibitors, and T-cell therapy. Chimeric antigen receptor (CAR)-T cells, one of the most popular cancer immunotherapy approaches in the last decade, are genetically engineered T-cells to redirect patients' immune responses to recognize and eliminate tumor-associated antigens (TAA)-expressing tumor cells. CAR-T cell therapy provides promising benefits in lung tumors. In this review, we summarize different immunotherapy approaches for lung cancer, the structure of CAR-T cells, currently undergoing CARs in clinical trials, and various TAAs are being investigated as potential targets in designing CAR-T cells for lung cancer.     

Brentuximab vedotin : nouvelle option thérapeutique dans la prise en charge des lymphomes CD30+

Brentuximab vedotin is a new antibody-drug conjugate composed of the anti-CD30 chimeric monoclonal antibody and the potent antimicrotubule drug monomethylauristatin E. In two phase II clinical trials, treatment with single-agent brentuximab vedotin resulted in response rates of 75% in relapsed/refractory Hodgkin lymphoma and 86% in relapsed/refractory systemic anaplastic large-cell lymphoma. Peripheral sensory neuropathy (40%) and neutropenia (20%) were the most frequent side effects, generally mild and manageable. After a large use in a compassionate program, brentuximab vedotin was approved in France in October 2012 for the treatment of Hodgkin lymphoma after failure of autologous stem cell transplantation or after failure of at least two prior multiagent chemotherapy regimens in patients non eligible for autologous transplantation, and for the treatment of systemic anaplastic large-cell lymphoma after failure of at least one prior multiagent chemotherapy regimen.     

Ongoing Development of Monoclonal Antibodies and Antibody Drug-Conjugates in Lymphoma

Rituximab, a monoclonal antibody (mAb) directed against CD20, has changed practices in the treatment of patients with B-cell lymphoma. The large success of rituximab has contributed to validate immunotherapy with monoclonal antibodies as a valuable strategy in lymphoma. Recently, better-engineered anti-CD20-mAbs have been designed to improve efficacy and safety. Also, new antibodies targeting other lymphoma subtypes including T-cell lymphoma and Hodgkin’s disease have been developed. Ongoing pharmacology development is concentrating on immuno-drug-conjugates combining the toxicity of chemotherapy, isotopes, or toxins with the specificity of mAbs. This article offers an overview on the development of new antibodies and immuno conjugates in lymphoma.     

Bexarotene: a clinical review

Bexarotene (Targretin^®, Ligand Pharmaceuticals Inc.) is a synthetic retinoid analog with specific affinity for the retinoid X receptor and belongs to a group of compounds called rexinoids. Early clinical trials of this drug demonstrated activity in cutaneous T-cell lymphoma. Subsequent Phase II/III trials have demonstrated a greater than 50% response rate in patients with all stages of cutaneous T-cell lymphoma who were refractory or intolerant to the previous therapy. The principal toxicities of bexarotene include central hypothyroidism, xeroderma and elevation of cholesterol and triglycerides. These toxicities can be managed with dose attenuation or addition of atorvastatin (Lipitor^®, Pfizer) or fenofibrate (TriCor?, Abbott Laboratories). Since bexarotene has little bone marrow toxicity, it is an excellent candidate for combination therapy with other modalities useful in the treatment of cutaneous T-cell lymphoma. These include ultraviolet B irradiation, psoralen and ultraviolet A photochemotherapy, interferons, denileukin diftitox (Ontak^®, Ligand Pharmaceuticals Inc.) and cytotoxic chemotherapy. Bexarotene has also been investigated in the treatment of breast cancer and non-small cell carcinoma of the lung with promising early results.     

Targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4): a novel strategy for the treatment of melanoma and other malignancies

Cancer immunotherapy centers on modulating the host's tumor-directed immune response. One promising approach involves augmentation of cell-mediated immunity by interrupting T-cell pathways responsible for immune down-regulation or tolerance. The discovery of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and its role as a key negative regulator for T cells has prompted efforts to target this signaling molecule to improve cancer therapy. Activation, or 'priming', of naive T cells in response to tumor-cell invasion comprises a dual-signaling mechanism. Signal 1 requires tumor-associated antigen recognition by the T-cell receptor, while signal 2 occurs through binding of CD80 or CD86 (B7.1 of 2) on the antigen presenting cell (APC) with CD28 on the T cell. Importantly, there is a final step responsible for naturally occurring immune regulation; this occurs in response to competitive binding of CD80/CD86 on the APC by CTLA-4 on the T cell. This 'immune checkpoint' interrupts signal 2 and inhibits the activated T cell. Targeting CTLA-4 as an anticancer strategy: Following proof-of-concept studies in animals, fully human anti-CTLA-4 antibodies were developed and 2 are undergoing clinical evaluation. Ipilimumab and tremelimumab have shown promising antitumor activity, initially in patients with advanced melanoma. Class-specific immune-related adverse events (irAEs) were common and mostly transient and/or manageable. These events are thought to be mechanism-of-action-related, indicating immune tolerance is broken; this relation may also explain the association between irAEs and response seen in several trials. Interruption of immune inhibitory pathways via CTLA-4 blockade appears to be a promising strategy for cancer immunotherapy.     

肿瘤免疫检查点治疗中的疾病暴发性进展及其应对策略

[摘要] 以PD-1/PD-L1 等免疫检查点为靶点,应用单克隆抗体加以阻断,从而达到激活免疫系统杀灭肿瘤的目的,是当今肿瘤生物治疗的重要手段。在部分肿瘤患者,免疫检查点抑制剂（ICIs）治疗可完全治愈或者有效抑制肿瘤,显著延长生存期;但是在部分肿瘤患者,ICIs 治疗导致病情加重,出现暴发性进展（HPD）的现象,即免疫检查点治疗后肿瘤发生反常的加速生长,首次评效时肿瘤生长速率（TGR）比治疗前增加大于50%（△TGR>50%）。本文重点讨论ICIs 治疗中HPD的相关问题,如HPD的发现过程、潜在的病理生理机制,以及未来如何应对这一挑战。