Could immunotherapy someday treat osteosarcoma?

By Naveed Saleh, MD, MS, for MDLinx
Published August 2, 2018

Key Takeaways

Different types of immunotherapy are emerging as potential treatments for osteosarcoma, according to a recent review in Pediatric Blood & Cancer.

“Several biological features of osteosarcoma suggest that modulation of the immune response could lead to benefits, and the wide variety of therapeutic approaches now available make this an exciting time for immunotherapy,” wrote the authors, led by Mary F. Wedekind, DO, Division of Hematology, Oncology, and Blood and Marrow Transplant, Nationwide Children's Hospital, Columbus, OH. Nevertheless, the vagaries of the immune system and the tumor microenvironment render the development of osteosarcoma immunotherapies highly challenging.

Osteosarcoma is the most common bone cancer, and it usually affects adolescents and young adults. Unfortunately, recent progress in treating this disease has been limited. This stagnation is analogous to that seen with adult solid tumors before the rise of immunotherapy. In the current review, the authors explore the rationale behind immunotherapy for osteosarcoma, current immunotherapies being tested in clinical trials, and emerging immunotherapies with possible osteosarcoma applications.

Experts suggest that immunotherapy could be effective in treating osteosarcoma for several reasons. First, osteosarcoma harbors an increased proportion of CD8+ infiltrating lymphocytes than do other sarcoma subtypes; this increased degree of infiltration is positively associated with survival.

Second, osteosarcoma tumors are genetically unstable, with some expressing programmed cell death protein-1 ligand (PD-L1), which could potentially be exploited by inhibitors of the programmed cell death protein-1 (PD-1)/PD-L1 axis. Third, various cell surface proteins present in osteosarcoma malignancies could possibly be targeted by antibodies.

For example, one form of osteosarcoma therapy that is currently approved for treatment in Europe is mifamurtide, which is a bacterial cell wall analogue that activates monocytes and macrophages, thus ameliorating tumor control.

“The interplay between the patient's immune system and cancer is complex and includes immune surveillance, immune cell infiltration, and tumor cytolysis by the host, which are counteracted by tumor defenses that dampen the immune response through the release of inhibitory cytokines and downregulation of surface markers,” the investigators wrote.

Cancer “immunoediting” is an immunotherapy paradigm compromising elimination, equilibrium, and escape. During elimination, some tumor cells fall prey to tumor-reactive T cells. Some cancer cells, however, enter an equilibrium stage during which tumor growth lies dormant. Other cancer cells manage to evade the immune system and multiply via various immunosuppressive mechanisms, including the following:

  • Loss of tumor antigen expression
  • Downregulation of human leukocyte antigens (HLA) on cancer cell surfaces, as well as recruitment of T-regulatory cells (Tregs)
  • Myeloid derived suppressor cells, or tumor-associated M2 macrophages

Such modifications could mediate the upregulation of inhibitory receptors (eg, cytotoxic T-lymphocyte associated protein-4 [CTLA-4] or PD-1) on T cells or the upregulation of inhibitory ligands (eg, PD-L1) on tumor cells. The goal of immunotherapy is to thwart the escape phase and jumpstart the patient’s immune system to identify and target cancer cells.

Antibodies—a stalwart of immunotherapy—are safe and readily available and have been used to treat many pediatric cancers. During “antibody-dependent cellular toxicity,” monoclonal antibodies (mAb) hook up to specific tumor surface antigens and trigger natural killer (NK) cells and macrophages to release cytotoxic granules to kill tumor cells.

Although several mAb against osteosarcoma have failed in clinical trials—possibly due to low expression of tumor antigens or aspects of the tumor microenvironment—researchers are now exploring the use of such antibodies vs other osteosarcoma cell surface proteins, including disialoganglioside (GD2), which is widely expressed in primary and secondary osteosarcoma tumors.

Tumor vaccines have long been investigated as a form of immunotherapy. They work by inducing antitumor responses via tumor antigen exposure. Dendritic cell (DC) vaccines are antigen presenting cells that can trigger T cells and mediate the amplification of cytotoxic T lymphocytes. Although DC vaccines have caused osteosarcoma tumors in animal models to regress, their effects in human patients have been limited.

Oncolytic viruses are attenuated and are intended to replicate only in malignant cells. The FDA approved talimogene laherparepvec (T-VEC) for melanoma, the first oncolytic virus to garner such approval. A clinical trial with T-VEC plus the anti-PD-1-antibody pembrolizumab is currently being investigated for treatment in sarcoma patients. Furthermore, other oncolytic viruses specifically designed to battle osteosarcoma are in preclinical development.

Adoptive cell therapy works by offering up cytolytic cells to yield an antitumor response. Some tumor cells can downregulate HLA and tumor antigen expression, which helps them evade the host’s immune system. T cells called chimeric antigen receptor T cells (CAR-Ts) have been engineered to not require HLAs for tumor recognition. In patients with osteosarcoma, clinical trials of CAR-Ts have resulted in some patients experiencing stable disease, along with no dose-limiting toxicities. Further studies are underway.

Tumor infiltrating lymphocytes (TILs) are another iteration of adoptive cell therapy. However, they are often unable to control tumors because cancer cells escape immune surveillance and response by using checkpoint ligands. According to the authors, checkpoint inhibitors—such as inhibitors of cytotoxic T-lymphocyte associated protein-4 (CTLA-4), whose expression is heightened in osteosarcoma—could counteract this process “by reinvigorating the T-cell-mediated antitumor responses against tumor antigens through the major histocompatibility complex.”

Nevertheless, the CTLA-4 inhibitor ipilimumab failed to demonstrate antitumor responses in a low-power, phase 1 clinical trial involving eight children with osteosarcoma. Other trials incorporating CTLA-4 inhibitors as part of combined inhibitor therapies are ongoing.

One final immunotherapy strategy detailed by the authors involves targeting immunosuppressive factors within the tumor microenvironment. For example, transforming growth factor-beta (TGF-β) is increased in metastatic or refractory osteosarcoma microenvironments, and its blockade has shown promise in animal (ie, preclinical) models.

One major challenge for developing cancer immunotherapies is the difficulty inherent in identifying predictive biomarkers. Another challenge derives from immune system complexity, and single-therapy approaches may not work as well as combined approaches.

“Although much work remains to be done,” the reviewers concluded, “the hope is that immunotherapy can lead to breakthroughs that will revolutionize osteosarcoma therapy in the same way that adult cancer therapy has been transformed.”

To read more about this study, click here

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