With the Food and Drug Administration and other worldwide regulatory authorities' approval of ipilimumab (Yervoy), sipuleucel-T (Provenge), nivolumab (Opdivo), and pembrolizumab (Keytruda), oncologic therapy has now moved into noncancer cell targets within the immune system. For many nonimmunologists, understanding how these vastly different therapies work to improve survival, like no other therapies have in the past, is a challenge. The present report reviews the normal function of the immune system, how cancers escape the normal immune system, and how these new therapies improve immune system reactions against cancers. The Oncologist 2016;21:233-243 Implications for Practice: Oncologists have tremendous experience with therapies that target the cancer cells. New biologic agents have been rapidly introduced recently that target not cancer cells, but the patient's immune cells. The mechanisms of action of these immune-based biologic agents are within the host immune system.To understand these new biologic therapies, basic knowledge of normal and abnormal immune function is essential. The present report explains the up-to-date basic immune normal and abnormal function and prepares the oncologist to understand how the new drugs work, why they work, and why there are associated adverse events.

Background. Chemotherapy‐associated thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (C‐TTP/HUS) is a condition involving thrombocytopenia, microangiopathic hemolytic anemia, and progressive renal dysfunction that develops in 2–10% of patients with a history of malignant neoplasms treated with certain chemotherapeutic agents. Pathogenesis of the disease may depend on the following: (1) generation of endothelial lesions in the kidney microvasculature, resulting from drug toxic effects and/or generation of small soluble circulating immune complexes (CIC), and (2) generation of autoantibodies and/or CIC that trigger aggregation and deposition of platelets around the lesions. Methods. Extracorporeal immunoadsorption treatment of plasma (PROSORBA columns, IMRÉ Corporation, Seattle, WA) to remove immunoglobulin G and CIC was evaluated in 55 patients for the potential to induce significant clinical benefits (increase in platelet count, decrease in hemolysis, stabilization of renal function) and longer survival. Results. Response to therapy was achieved in 25 of 55 patients examined. Response was associated with an estimated 1‐year survival rate of 61%, as compared with an estimated survival rate of only 22% in those who did not respond (P = 0.0001). Patients whose malignant neoplasms were in complete or partial remission at the time of development of C‐TTP/HUS had a significantly higher estimated 1‐year survival rate (74%) as compared with a historic control group of patients receiving other treatments (22%, P = 0.0161). Clinical responses were correlated with normalization of serum levels of CIC and complement components C3c and C4. There were no side effects associated with 75% of treatments. Immunoadsorption therapy was associated with generally mild to moderate manageable side effects, such as fever, chills, nausea/vomiting, respiratory symptoms, pain, hypertension, and hypotension, which were reported in 25% of procedures. Conclusions. This multicenter study establishes protein A immunoadsorption as an effective and safe treatment for cancer chemotherapy‐associated TTP/HUS, an otherwise fatal disease.

A phase 1/2 clinical trial evaluating dosing, safety, immunogenicity, and overall survival on metastatic colorectal cancer (mCRC) patients after immunotherapy with an advanced generation Ad5 [E1-, E2b-]-CEA(6D) vaccine was performed. We report our extended observations on long-term overall survival and further immune analyses on a subset of treated patients including assessment of cytolytic T cell responses, T-regulatory (Treg) to T-effector (Teff) cell ratios, flow cytometry on peripheral blood mononuclear cells (PBMC), and determination of HLA-A2 status. An overall survival of 20% (median survival of 11 months) was observed during long-term follow-up and no long-term adverse effects were reported. Cytolytic T cell responses increased after immunizations and cell-mediated immune (CMI) responses were induced whether or not patients were HLA-A2 positive or Ad5 immune. PBMC samples from a small subset of patients were available for follow-up immune analyses. It was observed that the levels of carcinoembryonic antigen (CEA) specific CMI activity decreased from their peak values during follow-up in 5 patients analyzed. Preliminary results revealed that activated CD4+ and CD8+ T cells were detected in a post immunization sample exhibiting high CMI activity. Treg to Teff cell ratios were assessed and samples from 3 of 5 patients exhibited a decrease in Treg to Teff cell ratio during the treatment protocol. Based upon the favorable safety and immunogenicity data obtained, we plan to perform an extensive immunologic and survival analysis on mCRC patients to be enrolled in a randomized/controlled clinical trial that investigates Ad5 [E1-, E2b-]-CEA(6D) as a single agent with booster immunizations.

A new intensive four drug combination chemotherapy regimen, termed PVeBV, consisting of cis-plathum, vinblastine, bleomycin, and VP-16, was administered to six previously untreated patients with poor prognosis advanced nonseminomatous testicular cancer and to four patients who had relapsed on primary platinum based regimens. The cis-platinum was administered in 250 ml of 3% saline at twice the dose (40 mg/m2 IV days 1-5 every three weeks) used in other treatment schedules. All six previously untreated patients achieved a complete remission. Four achieved a complete remission with three cycles of PVeBV while the other two patients achieved a complete remission with an additional cycle of cisplatinum and VP-16 at 200 mg/m2 IV X five followed by autologous bone marrow infusion. All four relapsed patients responded to PVeBV (two complete remissions and two partial remissions). There were no deaths associated with PVeBV therapy; however, myelosuppression was severe. There has been no renal toxicity (other than hypomagnesemia) observed with 35 cycles of highdose platinum therapy in previously untreated patients. These results indicate that PVeBV is a promising chemotherapy regimen for the treatment of poor prognosis testicular cancer patients. Furthermore, it appears that cis-platinum can be administered at higher doses than previously used without an increase in renal toxicity if administered in hypertonic saline. The highdose cis-platinum schedule, as used in PVeBV, warrants evaluation in other tumors which respond to standarddose platinum therapy.