Meet Our Researchers

Eliezer Van Allen

Associate Member at the Broad Institute
Assistant Professor at Harvard Medical School
The Question

Many new cancer immunotherapies, including inhibitors of the immune checkpoints PD-L1 and CTLA4, harness the patient’s immune system to attack tumors. These therapies have generated enormous excitement in recent years because of the dramatic and lasting responses some patients have had. Indeed, a small number of patients with widely metastatic solid tumors, like lung cancer and melanoma, have been effectively cured after immunotherapy treatment.

However, there are still many questions surrounding these new therapies. We do not understand why these patients have exceptional responses—and why most patients do not. Uncovering the mechanism of these responses could allow us to improve cancer treatment by identifying those patients who would benefit from these therapies and finding ways to enhance the effectiveness of these drugs in patients without extraordinary responses.

The Approach

To achieve this scientific goal, our team has leveraged BroadIgnite funds to identify patients with exceptional responses to immunotherapies and then to perform comprehensive genomic studies on tumor samples from them to uncover the mechanisms behind their responses. We sequenced the entire protein-coding genome (whole exome) and expressed genes (transcriptome) of tumors and normal body cells from our patients. We also sequenced the resistant tumors of patients who ultimately stopped responding to these agents.

The Results

The patients we have studied through BroadIgnite have many different types of cancer—leiomyosarcoma (cancer of the connective or supportive tissues), anal squamous cell carcinomas, and cancers of the kidney and prostate. In many of these cases, we have been able to identify the mechanism of response or resistance. For example, we have identified the involvement of the PI3K pathway and patient-specific mutations in leiomyosarcoma that becomes resistant to immunotherapy.

Our findings provide rare insight into the interactions between tumors and treatments. They also hint at how we could harness the tumor’s own properties to prevent resistance from occurring and expand the usefulness of these therapies in combination with other drugs. For example, we identified a genetic lesion that gave rise to a tumor-associated antigen specific to the patient with leiomyosarcoma. This antigen not only provoked the patient’s own immune cells, effectively enlisting them to fight the cancer, but also disappeared in the resistant tumor, suggesting that tumor cells adapted to evade the immune system.

We have already begun to document these results so that we can share our exciting results with the scientific community and drive new avenues of development of cancer immunotherapies.