1. Vidaurri, Vincent

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In 1998, interleukin-2 sat alone in the circle of immunotherapy, and now that circle has expanded to include a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), three programmed cell death-1 (PD-1) checkpoint inhibitors, three programmed death-ligand 1 (PD-L1) checkpoint blockers, and adoptive cell transfer. As the circle of immuno-oncology drugs expanded, the types of cancers responding to therapy also swelled, and although these advancements have transformed cancer care, many epithelial cancers do not respond to immunotherapy.

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"One problem with the checkpoint modulators is they are relatively ineffective against the common epithelial cancers that result in 550,000 deaths in America," said Steven A. Rosenberg, MD, PhD, Chief of Surgery at the NCI and Professor of Surgery at the Uniformed Services University of Health Sciences and the George Washington University School of Medicine and Health Sciences.


"Anti-CTLA-4 and PD-1 work well in melanoma, but they don't work well in colon, pancreatic, and a lot other cancers, so there is plenty of unmet need," added Richard Miller, MD, Adjunct Professor of Medicine (Oncology) at Stanford Medical School.


To meet this need, the circle of immunotherapy will widen to include new checkpoint blockers against adenosine and new adoptive cell therapy methods.


Adenosinergic Pathway

The adenosinergic pathway mediates inflammation and immunosuppression within the tumor microenvironment. The tumor cell necrosis, which generates high ATP concentrations, and ecto-ATPDase CD39, turns this ATP into AMP. CD73, an anchored cell surface ectonucleotidase enzyme, converts AMP to adenosine. Adenosine hinders lymphocyte and myeloid cell activity by binding to adenosine A2A receptors (Immunol Lett 2019;205:31-39).


Strategies to inhibit adenosine activity follow two approaches: 1) blocking CD73 enzymatic activity, and 2) inhibiting adenosine A2A receptor activation.


CD73 Modulation

CD73 not only converts AMP to adenosine but, upon conformational change, it energizes lymphocytes and helps with lymphocyte adhesion and migration. To take advantage of CD73 multiple functions, CPI-006, an investigational monoclonal antibody, was developed. CPI-006 promotes immunostimulation through its dual mechanism of inhibiting CD73 production of adenosine and upregulating lymphocyte activity.


Adenosine A2A Receptor Antagonist

Ciforadenant, formerly CPI-444, is an oral small molecule antagonist of adenosine A2A receptor. At the Society for Immunotherapy of Cancer's 2018 annual meeting, researchers reported its phase I/Ib results. The study investigated ciforadenant monotherapy and ciforadenant combined with atezolizumab in the treatment of multiple recurrent renal cell carcinoma patients, most having failed prior immunotherapy. Data showed the following:


* Disease control at 6 months was reached in 17 percent in the monotherapy group and 35 percent in the combination group.


* Progression-free survival was 4.0 months and 5.9 months of patient receiving monotherapy and combination therapy, respectively.


* At 20 plus months, the overall survival was 88 percent in the combination therapy and at 16-plus months the overall survival was 65 percent for monotherapy.



In a 2019 ASCO presentation, administration of CPI-006 to patients with advanced refractory cancers was shown to effect the migration and activation of lymphocytes. As monotherapies, CPI-006 and ciforadenant demonstrate anti-tumor activity, but their activities improved when combined together (J Clin Oncol 2019;37:suppl; abstr 2505). Current investigational studies are exploring whether triple combination (CPI-006, ciforadenant, and an anti-PD-1 or anti-PD-L1) will further improve response.


Adoptive Cell Therapy

"Adoptive cell therapy (ACT) has the greatest hope for major advances in the future," said Rosenberg. "We're in the midst of developing adoptive cell therapies for the common epithelial cancers that result in 90 percent of all cancer deaths in this country for which we have few effective treatments."


ACT transfers autologous lymphocytes into a patient, and these lymphocytes recognize antigens on the tumor and mediate tumor regression. To accomplish this, ACT pursues two approaches: 1) engineering chimeric antigen receptor T cells (CAR T), and 2) transferring large populations of naturally occurring somatic mutation reactive T cells.


"Unfortunately, the CAR T-cell approach is unlikely to be effective for any of the solid tumors because CAR T recognizes cell surface antigens and there are virtually no antigens unique to cancer that aren't on normal cells," said Rosenberg.


Lymphocytes are present at the tumor site, but it was unknown until recently what antigens these lymphocytes recognized on the tumor.


"It turns out tumor-infiltrating lymphocytes recognize the products of tumor mutations. And by targeting the selective mutations within each patient's cancer, we can mediate cancer regression," said Rosenberg. "It's ironic that the mutations that cause the cancer are the targets of effective therapy."


To capitalize on this carcinogenic process, the somatic mutation reactive T cells identify and attack unique antigens, called neoantigens, specific to the tumor. The goal is to transfer a polyclonal population of lymphocytes (both CD4+ and CD8+) that recognize multiple neoantigens and also create a pool of long-term lymphocytes, providing indefinite defense. That is, the therapy targets the unique mutational signature for that tumor for that patient-precision and personalized medicine incarnate.


"What has us most excited is we have shown that multiple different cancer histologies can respond to this. And the potential exists for this therapy to be applied to many different cancer types," said Rosenberg.


This adoptive cell therapy resulted in a durable regression in a patient with metastatic cholangiocarcinoma (Science 2014;344:641-645). Targeting KRAS mutations, it also mediated a durable regression in a patient with metastatic colorectal cancer (N Engl J Med 2016;375:2255-2262). When used in conjunction with IL-2 and a checkpoint blocker, it caused a complete durable regression in a chemorefractory hormone receptor-positive patient with metastatic breast cancer (Nat Med 2018;24:724-730).


"For the first time, we have an immunotherapy that can potentially impact cancers, irrespective of the cancer diagnosis, though much developmental work remains to be done," Rosenberg noted.



"The next wave of immunotherapy will involve new targets, pharmacodynamic markers, and creative and methodical clinical designs to put these immuno-oncology agents together in a rational way for the right disease," said Miller.


The future of immunotherapy is promising. New immuno-oncology agents will continue to be developed, and the largest gains will be in finding the right combination, whether that's a doublet (CP-006 with ciforadenant), a triplet (CP-006, ciforadenant, and anti-PD-1), or quadruplet (CP-006, ciforadenant, anti-PD-1, and SMR-T). Given the rapidly expanding circle of immunotherapy, the beginning of the end is near.


Vincent Vidaurri is a contributing writer.