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New Research - Osteosarcoma Treatment

Enhanced Immunotherapy Targeting ALPL-Expressing Osteosarcoma Using CAR-T Cells

Rayan Afif | CERI Youth Program and CERI Research Team Member, and 
Aygün Sahin, MSc, PhD  | CEO, President, and Cancer Lead, Cancer Education and Research Institute (CERI)

Enhanced Immunotherapy Targeting ALPL-Expressing Osteosarcoma Using CAR-T Cells

Osteosarcoma is a malignant bone tumor that is not easy to treat especially when it highly expresses alkaline phosphatase (ALPL). This article explores the use of CAR-T cells (chimeric antigen receptor-expressing T cells) engineered to target ALPL-expressing osteosarcoma cells. The strategies presented in the study also describe several in vitro and in vivo methods to evaluate the capacity of these CAR-T cells to eradicate osteosarcoma tumors and enhance the therapy results.

What is sarcoma?

Sarcomas are tumors that originate in the bones and connective tissues which comprise of bone, muscles, fat, and cartilage [1]. They are not very frequent compared to carcinomas, which are cancers originating from epithelia but include a wide range of cancers that can develop in anyone at any age. It makes up for about 20% of all childhood cancers but only 1% of all adult cancers [1].

What is osteosarcoma?

Osteosarcoma is a bone cancer most commonly diagnosed in young people [2]. Osteosarcoma makes up 30% of all bone sarcoma diagnoses and is mostly diagnosed in teenagers and young people under the age of 25. It is referred to as the formation of immature bone or osteoid tissue by tumor cells. Despite all these achievements, the survival rate for patients diagnosed with advanced or metastatic osteosarcoma remains rather low and this underscores the necessity for the development of new therapeutic strategies [3]. 

What is ALPL-expressing osteosarcoma?

ALPL-expressing osteosarcoma can be categorized mainly due to the expression of alkaline phosphatase (ALPL)(1), an enzyme that plays a part in bone mineralization [3]. The ALPL levels are usually elevated in these tumors and therefore become a target for immunotherapy where the immune cells are preferentially recruited to attack the cancer cells without affecting the other normal cells in the body [3].

What is a CAR-T cell?

CAR-T cells (2) are autologous T cells (3) or allogeneic T cells (4) that have been genetically engineered to include a chimeric antigen receptor (CAR) that is specific to an antigen present on a patient’s tumor cells [3]. These engineered T cells are injected or reinjected (based on whether the CAR-T cells are allogeneic or autologous, respectively) into the patient’s body where they attach themselves to the cancer cells that display the target antigen and eliminate them. CAR-T cell therapy has been effective especially for some blood diseases; however, the question of its effectiveness for solid tumors such as synovial sarcoma is still under research [1].

Using CAR-T cells to target ALPL in Osteosarcoma

In this particular experiment, CAR-T cells were designed to recognize and bind to ALPL which is present on the osteosarcoma cells only [3]. Herein, cell function and cytotoxicity of these ALPL-targeted CAR-T cells were tested by several in vitro and in vivo assays. Thus, the study proved that CAR-T cells targeted and eliminated ALPL-positive osteosarcoma cells through cytokine release assays, bioluminescence-based eliminating assays, and proliferation studies [3].

Additionally, these CAR-T cells depicted the ability to effectively eliminate the osteosarcoma primary cells and exhibited highly effective anti-tumor functionalities in xenograft mice models (5) [3]. This implies that CAR-T cells directed to ALPL can destroy and diminish osteosarcoma tumors in animal models hence offering another therapeutic approach.

What does the study show?

Looking at the specific treatment through CAR-T cells, the study focuses on using CAR-T cells to target ALPL-positive osteosarcoma. Key findings are as follow:
  • CAR-T Cell Efficacy: ALPL is expressed in osteosarcoma cells and the developed CAR-T cells were observed to selectively recognize and reduce these target cells with high efficacy in vitro and in vivo [3].
  • In Vivo Results: The outcomes of CAR-T cells in xenograft mouse models were to lessen tumor size and lessen the quantity of osteosarcoma cells indicating significant anti-tumor activity [3].
  • Statistical Analysis: In analyzing the results of the study to compare the treated and control groups, the Mann-Whitney test demonstrated the likelihood of tumor reduction to be statistically significant, thus confirming the success of CAR-T therapy [3].
All in all, the present study provides evidence that CAR-T cells have therapeutic potential for osteosarcoma with high ALPL expression.

Importance of the Study for osteosarcoma

This research is a major breakthrough in the efforts being made to find an effective treatment for osteosarcoma through immunotherapy, based on the data obtained from in vitro assays and animal experiments. ALPL-directed CAR-T cells seek out the tumor-associated antigen, ALPL, on the surface of this lethal cancer type, osteosarcoma, making this treatment more selective to the aggressive form of cancer. 

This therapy could help patients diagnosed with osteosarcoma, and especially those, in whose tumors ALPL levels are high. Such an approach could set the stage for additional studies of clinical trials and would open a door to start a new therapeutic approach for osteosarcoma patients [3].

References:

  1. Afif, R and Sahin, A. Advancing CAR-T Cell Therapy for Synovial Sarcoma: Afami-cel's Promising Results. Cancer Education and Research Institute (CERI). https://www.canceredinstitute.org/new-research-synovial-sarcoma-treatment.html (accessed on July 25, 2024)
  2. Sahin, A. Sarcoma. Cancer Education and Research Institute (CERI). https://www.canceredinstitute.org/sarcoma (accessed on July 25, 2024)
  3. Tam, Y.B., Low, K., PS, H. et al. Proteomic features of soft tissue tumours in adolescents and young adults. Commun Med 4, 93 (2024). https://doi.org/10.1038/s43856-024-00522-x  (accessed on July 25, 2024)

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Learn about the FIRST CAR-T cell, ​Afami-cel, therapy approval for Synovial Sarcoma - 
​Afami-cel's Promising Results

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