Cancer Clonal Theory, Immune Escape, and Their Evolving Roles in Cancer Multi-Agent Therapeutics.

PURPOSE OF REVIEW: The knowledge base of malignant cell growth and resulting targets is rapidly increasing every day. Clonal theory is essential to understand the changes required for a cell to become malignant. These changes are then clues to therapeutic intervention strategies. Immune system optimization is a critical piece to find, recognize, and eliminate all cancer cells from the host. Only by administering (1) multiple therapies that counteract the cancer cell's mutational and externally induced survival traits and (2) by augmenting the immune system to combat immune suppression processes and by enhancing specific tumor trait recognition can cancer begin to be treated with a truly targeted focus. RECENT FINDINGS: Since the sequencing of the human genome during the 1990s, steady progress in understanding genetic alterations and gene product functions are being unraveled. In cancer, this is proceeding very fast and demonstrates that genetic mutations occur very rapidly to allow for selection of survival traits within various cancer clones. Hundreds of mutations have been identified in single individual cancers, but spread across many clones in the patient's body. Precision oncology will require accurate measurement of these cancer survival-benefiting mutations to develop strategies for effective therapy. Inhibiting these cellular mechanisms is a first step, but these malignant cells need to be eliminated by the host's mechanisms, which we are learning to direct more specifically. Cancer is one of the most complicated cellular aberrations humans have encountered. Rapidly developing significant survival traits require prompt, repeated, and total body measurements of these attributes to effectively develop multi-agent treatment of the individual's malignancy. Focused drug development to inhibit these beneficial mutations is critical to slowing cancer cell growth and, perhaps, triggering apoptosis. In many cases, activation and targeting of the immune system to kill the remaining malignant cells is essential to a cure.

How Cancers Escape Immune Destruction and Mechanisms of Action for the New Significantly Active Immune Therapies: Helping Nonimmunologists Decipher Recent Advances.

UNLABELLED: 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. 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.

Extended evaluation of a phase 1/2 trial on dosing, safety, immunogenicity, and overall survival after immunizations with an advanced-generation Ad5 [E1-, E2b-]-CEA(6D) vaccine in late-stage colorectal cancer.

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 (PBMCs), and determination of HLA-A2 status. An overall survival of 20 % (median survival 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 five 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 three of five 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.