1. Fuerst, Mark L.

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BOSTON-Combination of immunotherapeutic agents is the wave of future cancer treatment. Cellular mechanisms of cancer show complexity and may need blockade of both PD-1 and cytotoxic T-lymphocyte associated protein-4 (CTLA-4) to enact cures.


"We are on the verge of being able to cure some kinds of cancer. With some hard work, we can make a lot of progress over the next few years," said Jim Allison, PhD, Director, Parker Institute of Cancer Therapy, at the American Association for Cancer Research International Meeting on Advances in Malignant Lymphoma.


Allison outlined an understanding of the fundamental mechanisms of T-cell activation and regulation in his presentation, "Immune checkpoint blockade in cancer therapy: new insights, opportunities, and prospects for cure."


Immune Checkpoint Blockade

Cancer has myriad gene mutations and high genome instability, and is many different diseases, each with distinct genetic alterations. "Targeting single mutations with targeted inhibitors almost always leads to disease relapse," said Allison. That's why immunotherapy may be a good choice to treat cancer. Immune checkpoint blockade is a paradigm shift in cancer therapy.


"It doesn't target tumor cells, doesn't involve vaccines or cytokines to turn on immune responses, and works by blocking inhibitory pathways to unleash anti-tumor immune responses," noted Allison. This includes dynamic integration of T-cell receptor and costimulatory signals.


The FDA has approved immune checkpoint blockade in more than a handful of conditions, including melanoma (including as adjuvant therapy and for pediatric patients), non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), Hodgkin lymphoma, bladder cancer, head and neck cancer, Merkle cell carcinoma, MSI-high colorectal cancer, gastric/gastroesophageal cancer, and hepatocellular carcinoma.


CTLA-4 blockade enhances tumor-specific immune responses. Ipilimumab, a fully human antibody to CTLA-4, elicits objective tumor responses in many tumor types, including melanoma, prostate, kidney, bladder, ovarian, and lung cancers. Adverse events, including colitis, hepatitis, and hypophysitis, are serious but generally manageable, Allison said. Very rare side effects include type 1 diabetes and myocarditis.


The role of PD-1 in cancer immune evasion is well-established, and monoclonal antibodies targeting PD-1 are known to boost the immune system for the treatment of cancer. Anti-PD-1 phase I data with nivolumab showed it had clinical activity in melanoma, NSCLC, RCC, and colorectal cancer, with adverse events similar to ipilimumab.


He noted that anti-CTLA-4 and anti-PD-1 therapies are inherently different. "Anti-CTLA-4 is hard wired, targets the CD28 pathway, works during priming, and expands clonal diversity. It primarily affects CD4 T cells, can move T cells into 'cold' tumors, response is often slow, adverse events are relatively frequent, and disease recurrences after responses are rare."


In contrast, anti-PD-1 "induces resistance, targets the TCR pathway, works on exhausted T cells, does not expand clonal diversity. It primarily affects CD8 T cells, does not move T cells into tumors, responses are usually rapid, adverse events less frequent, and disease recurrence after response is significant," he explained.


Looking Forward

"Where do we go from here?" asked Allison. Combination of immunotherapies is one answer, such as ipilimumab plus nivolumab, which has proven better than ipilimumab alone in metastatic melanoma.


Allison outlined critical issues for further clinical development of immune checkpoint targeting. These include:


* determination of cellular and molecular mechanisms involved in the anti-tumor effect;


* determination of the impact of other therapeutic agents on the immune system;


* combining the best standard-of-care therapies with immune checkpoint agents;


* targeting new molecules to improve efficacy; and


* identification of predictive, prognostic pharmacodynamics biomarkers.



"We are rethinking clinical trial design to obtain appropriate samples for laboratory studies," he said. Cancer immunotherapy trials and laboratory interrogation have been combined in a translational immunotherapy research program, called the Immunotherapy Platform, developed at MD Anderson Cancer Center, Houston.


As of January 2018, the program is participating in more than 107 ongoing clinical trials across 18 MD Anderson departments, and 3,253 patients have been enrolled to date. Longitudinal samples, including 8,226 blood samples, 2,452 fresh solid tumor tissue samples, and 1,476 hematologic tumor samples, have been collected and analyzed.


Other researchers are examining ipilimumab plus radiation therapy in castration-resistant prostate cancer for potential characteristics of immunogenic and non-immunogenic tumors. A prostate cancer pre-surgical combination study includes anti-CTLA-4 therapy plus hormonal therapy in a clinical trial of 20 patients with localized disease.


One idea is to discover how to convert a "cold" prostate tumor microenvironment to a "hot" one. "Resistance mechanisms involving immune cells include additional immune inhibitory pathways in prostate cancer microenvironment after ipilimumab treatment," said Allison. Researchers are looking at PD-L1 expression and VISTA expression in prostate cancer after ipilimumab treatment and how to overcome resistance of prostate cancer with anti-CTLA-4 plus anti-PD-1 therapy.


"Can we identify checkpoint blockade responsive T-cell populations?" Allison asked. Studies show that checkpoint blockade modulates MC38 infiltrating T-cell population frequencies, he noted.


In summary, Allison stated, "the therapeutic mechanisms of CTLA-4 and PD-1 are distinct. These mechanisms are the same in a highly immunogenic and poorly immunogenic tumor. These distinct mechanisms may explain why the combination is so effective. Specific CD4 and CD8 T-cell subtypes contribute to the therapeutic effects in both therapies. Monitoring these subtypes rather than total CD4 or CD8 cells correlates better with outcome and may be much more predictive of outcome."


Co-stimulation may play a role in regulation of T-cell differentiation. Researchers have identified unusual inducible co-stimulator-positive Th-1-like CD4 cells that arise after CTLA-4 blockade. In clinical studies, these cells have shown a 2-10 fold increase in tumor and blood after ipilimumab. They contain tumor-specific interferon gamma and tumor necrosis factor-alfa-producing CD4 cells. "An increase is associated with longer survival. It may be a pharmacodynamic marker of ipilimumab activity. Engaging the inducible co-stimuIator pathway with agonist vaccine increases efficacy of anti-CTLA-4," said Allison.


Novel targets for future immunotherapies include dendritic cells, peripheral tissue tumors, tissue macrophages, and regulator T-cells. They all interact with effector T-cell proliferation and function, he noted.


"Combinations to enhance checkpoint targeting result in cures. These combinations block multiple checkpoints (negative and positive) and enhance innate immunity. They include oncolytic viruses, local ablation, blocking of other immunosuppressive factors, conventional therapies, radiation, vaccines, and genomically targeted therapies," said Allison.


Mark L. Fuerst is a contributing writer.