1.4 Clinical Progress in Tumor Immunotherapy
Immunotherapy is now widely established as a potent and effective treatment option across several types of cancer.Since the first FDA-approval of ipilimumab treatment in solid malignancies had been significantly impacted by the introduction of immunotherapy particularly with immune checkpoint inhibitors, immunotherapy was most transformative in the management and treatment of melanoma.Advanced or metastatic melanoma has always been considered the most virulent and resistant of all cancers, with dismal survival rates.The incidence of melanoma is currently on the rise with one-fifth of the diagnosed patients expected to develop metastatic disease.Treatment options were limited and included toxic chemotherapy and interferon treatments which had deleterious side effects, including hypertriglyceridemia, hyperuricemia, hepatotoxicity, flu like symptoms, depressive mood disorder, suicidal thoughts among many others.One-year survival rate 25.5% and a 6.2-month median survival duration.Ten-year survival rates improved to 22% with the monoclonal antibody directed against CTLA-4, compared to historical control of 10%.KEYNOTE-001 trial of pembrolizumab in patients with advanced/metastatic melanoma,demonstrated an improved 5-year overall survival rate (OS) to 34% in all patients and 41% in treatment-naive patients.The study was one of the first to depict how much we have evolved in treating metastatic melanoma and with more tolerable irAEs.Various immunotherapies used in clinical practice and the year they were approved for clinical use are summarized[18].
For advanced stage head and neck cancers, cytotoxic chemotherapy is still the first line treatment and prognosis is bad for patients who progress during treatment.Second line therapeutic options were limited, until the advent of introduction of immune checkpoint inhibitors.Nivolumab was the first immunotherapy US FDA-approved in head and neck cancers because of the results from CheckMate-141, followed by pembrolizumab with the US FDA approval for second-line therapy because of the results from KEYNOTE-40 [18].
In most cases, esophageal cancer is a treatable disease, but it is rarely curable in advanced or metastatic disease.Esophageal cancer is not as common in the U.S., but it has limited treatment options and prognosis is poor.Survival rates at 5 years for advanced stages esophageal cancer, is typically 5%-20%.Breakthrough in the search for effective second line treatment of patients with advanced esophageal cancers, came from findings of the KEYNOTE-181 trial.Results demonstrated pembrolizumab improve OS in patients with PDL1 combined positive score (CPS)＞10.CPS was developed to evaluate the number of PD-L1 staining cells relative to all viable tumor cells, and it has become a surrogate marker for patients who may benefit from treatment with pembrolizumab.The role of combination pembrolizumab and cytotoxic chemotherapy in esophageal cancers, is currently being studied in the frontline setting in an ongoing phase III trial,KEYNOTE-811 trial.In a phase II trial of patients with untreated metastatic gastric,gastroesophageal junctional and esophageal cancers overexpressing HER2NEU, the role of immune checkpoint inhibitor in combination with trastuzumab (monoclonal antibody against HER2NEU)has demonstrated preliminary promising results, with median progression free survival reaching 11 months.(https://www.daowen.com)
Dramatic improvement in survival benefits with immunotherapy compared to cytotoxic chemotherapy in lung cancers and melanoma, has led to the expanded development of immunotherapy in hematologic malignancies.In recent years, the paradigm for treatment of hematologic malignancies had dramatically changed.Gone are the days when fludarabine based combination chemotherapy was used to treat chronic lymphocytic leukemia (CLL).Imagine the toxicity of chemotherapy compared to the newer treatment options in the form of immunotherapy.Ibrutinib is a small molecular drug that irreversibly binds to an important B cell enzyme, Bruton’s tyrosine kinase (BTK).It is essentially the wonder drug being currently used to treat B-cell cancers like CLL, mantle cell lymphoma, and Wald Enstrom’s macroglobulinemia, giving patients an effective chemotherapy-free option.Improved survival outcomes in both RESONA TE 2 comparing ibrutinib with chlorambucil and iLLUMINA TE comparing combination ibrutinib with obinutuzumab (fully humanized CD20 targeted monoclonal antibody) with standard chemoimmunotherapy regimen, validated current use of ibrutinib in front-line setting for patients with CLL.Additionally, the results of the iLLUMINA TE trial continued to show progression free survival benefit even in high risk sub-groups (del17p or TP53 mutation, del11q or unmutated IGHV)compared with standard chemoimmunotherapy arm [18, 20].
In classic Hodgkin lymphoma (cHL), investigators have evaluated the role of check point inhibitors to improve response rates.Pembrolizumab is another humanized IgG4 isotype antibody that binds to PD-1 located on lymphocytes and blocks the interaction of PD-L1 and PD-1.Results from KEYNOTE-087 demonstrated that treating patients with relapsed refractory classic Hodgkin lymphoma with pembrolizumab, improved overall response rate.Similarly, treatment with combination of nivolumab and brentuximab vedotin, resulted in improved response rates for cHL patients in first relapse and relapsing post-transplant.Based on these results and advances,anti-PD-1 antibodies have now been approved by the US FDA for cHL patients with relapse and/or refractory diseases [18, 21].
Immune checkpoint inhibitors are but one-way modulation of immune system infiltrate and revolutionize cancer care.Another success in immunotherapy is with chimeric antigen receptor(CAR) T-cell therapy.CAR T-cell therapy is considered the most innovative example in personalized cancer medicine.This is a type of treatment in which a patient’s own T-cells are changed in the laboratory so they will specifically attack that patient’s cancer cells.These T-cells are taken from a patient’s blood.Then the gene for a special receptor that binds to a certain protein on the patient’s cancer cells is added in the laboratory, to genetically programmed and trained the T-cells to attack cancer cells.The special receptor is called a chimeric antigen receptor.Large numbers of the CAR T-cells are grown in the laboratory and infused back into the patient.CAR T-cell therapy has been approved by the US FDA for certain types of lymphoma and leukemia since 2017.Results from ZUMA-1 endorsed the US FDA approval of axicabtagene ciloleucel (CD 19 directed CAR T-cell therapy) for patients with relapsed, refractory diffuse large B-cell lymphoma,follicular lymphoma with transformation and high-grade B-cell lymphoma with failure of two prior systemic lines of therapy.Tisagenlecleucel is another CD19-directed CAR T-cell therapy which was the US FDA-approved and currently being used for treatment of patients with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse.Complete response rates were 80%-90% in this sub-group, however the relapse free survival declined to 60% in the 12 months and these are thought to be due to early CAR T-cell loss, also called T-cell exhaustion.Investigators are currently studying the use of immune checkpoint inhibitors in combination with CAR T-cell therapy to determine if the persistence of T-cell can be sustained, hence improving relapsed free survival [18, 22].Immunotherapy is currently becoming the new foundation stone in treatment of various malignancies and more recent clinical guidelines are constantly being updated to incorporate immunotherapy in the mix.Having achieved this status in cancer treatment starting from melanoma then lung cancer and now other cancers, we can only hope for better and better results in all cancer types including hematologic malignancies.New clinical trials are looking to enhance the excellent current clinical response rates achieved by immunotherapy and finding ways to overcome the known and unknown immune resistance pathways.With immunotherapy we are in the right direction and are looking forward to the day when cancer will just be called a chronic disease [18].