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Meet the Researcher: Dr. Robert Vonderheide

BCRF’s Dr. Vonderheide describes the promises and challenges of immunotherapy in breast cancer

After studying immunology as a graduate student, Dr. Robert Vonderheide was so amazed by its complexity and potential in medicine that he decided to go to medical school. As a medical oncologist, Dr. Vonderheide combines basic research and clinical investigation to advance the understanding of tumor immunology and to develop novel immunotherapies for cancer, with a focus on breast cancer. 

In acknowledgement of Triple Negative Breast Cancer Day on March 3, Dr. Vonderheide spoke with us about the promise and challenge of immunotherapy in breast cancer, particularly triple negative breast cancer, TNBC.

An Early Believer in the Power of Immunotherapy

I remember listening to my medical school lectures through the lens of immunology, confident that there had to be an application for immunotherapy in medicine. As an oncology fellow, I was fascinated by the emerging field of cancer immunotherapy, and it was during my time as a postdoc that I began to work on a preventive cancer vaccine.

I remember cancer meetings not too long ago, when immunology wasn't a central part of the conversation but there was a smaller group of investigators hoping that continued research would reveal new options.   

I think in 2017 that we've reached the “end of the beginning” of cancer immunotherapy. By that, I mean that we now have multiple FDA-approved immunotherapy agents with more on the way which in some cases, lung cancer for instance, are superior to chemotherapy. That is an amazing development, and in many ways a “20-year overnight sensation”. Now we can look forward with the realistic expectation that under the right conditions, the body's own immune system can treat cancer. We are now rediscovering some of the immune therapy approaches that by themselves did not meet clinical efficacy previously, particularly in breast cancer, and looking to new combinations.

We've learned two important things:

1. The immune system is part of the natural history of breast cancer, particularly TNBC

2. The immuno-biology of breast cancer is not the same as melanoma, for example, and so the approaches that can work for patients with melanoma may not work for most patients with breast cancer.

A Moment of an Incredible Opportunity

We think that vaccines will play an important part of immunotherapy in breast cancer, but not by themselves.  While clinical trials have not shown the type of efficacy in breast cancer that we know is possible, what they have shown is that we can re-educate the patient's immune system with vaccines to recognize breast cancer cells and initiate an immune response. What we didn't realize during those first clinical trials was that the immune response being generated wasn't sufficient. It needed help.

What we've learned from lung cancer and melanoma is that the checkpoint inhibitors (anti-PD1/PD-L1 and CTLA4 agents) re-invigorate an existing T-cell responses, but if the T-cell response is absent or insufficient in a particular patient, the drugs may not work.  For those patients, we need to start an immune response and that's what vaccines do.

Now we have both pieces. We can start the immune response with vaccine and follow it with checkpoint therapies. Combinations of vaccine and checkpoint blockade are the next frontier in immuno-oncology and there is no better place to start than in triple negative breast cancer. We already know there is a fraction of patients who respond and we can build on that.

When I say "vaccine", I am not limiting that to only classical vaccines. There are other ways to "vaccinate" a patient against his or her cancer.  For example, radiotherapy injures the tumor cell and awakens an immune response. Our BCRF research has shown that the combination of radiotherapy with immunotherapy is synergistic. We have a clinical trial[1] in which patients with metastatic breast cancer receive specialized radiation to one tumor lesion followed in combination with two different checkpoint inhibitors. Our early results in this trial are promising but we have much more work to do.

Adding a New Dimension to Precision Medicine

Over the last five years, we have witnessed the power of the immune system and have gained confidence that immunotherapy is a way forward; it is another tool in the fight against cancer, but it is very complicated. I think the new c generations of immune therapies that will work in breast cancer will be combinations and will need to address the unique immuno-biology of breast cancer. Adding to that complexity, we don't fully understand how immune system responds to breast cancer and how responses vary from patient to patient despite being given the same medication.  That will require immune profiling - understanding not only the mutations that are driving tumor growth, but also other mutations and gene abnormalities that may make the tumor more or less recognizable to the immune system. Immune profiling will help us to understand the immune landscape around the tumor, the immune cell types, and the surrounding tumor stroma.

Imagine if we could understand, in real time, not only the gene mutations in a particular breast tumor but also all the information about immune activation and immune suppression. That information could potentially tell us how to tailor an immune therapy for that particular patient.  We're already approaching this for patients with melanoma, but we have to work harder for patients with breast cancer.

One approach will be to adapt the state-of-the-art immune techniques that have been so successful in basic laboratories lab and apply these approaches in the clinical setting- just like the field did with next generation tumor sequencing a decade ago.

Knowing When We've Made It

I think we'll know we're there when we can use immune profiling to predict which TNBC patients are likely to respond to checkpoint inhibitors and which aren't. This is happening in other tumor types, but we still need to do that work in breast cancer.

We'll know we're there in breast cancer when:

  • We can use immune profiling to identify patients up front who are likely to respond to immune therapy;
  • We understand why a patient who initially responds to immune therapy stops responding;
  • We are able to decipher features of a patient's immune system, independent of the cancer,  that predisposes him or her to responding (or not) to immune therapy
  • We can we tailor immunotherapy to give the most effective therapy to those who will respond and lessen risk of toxicity by not giving therapy to those who will not respond.

There is also the potential to discover completely new immune pathways that make sense for TNBC. Our group is looking at this now by studying TCGA data. We are already seeing a mosaic of mutations and gene expression patterns that tells us that the immune reactivity and immune response is different for every woman's breast cancer.

Interested in learning about about triple negative breast cancer? Dr. Vonderheide along with BCRF researcher Dr. Leisha Emens recently shared their insights on TNBC research with us. Read their in-depth conversation here.  

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Dr. Vonderheide and BCRF colleague Dr. Susan Domchek have several ongoing clinical trials testing immune therapy approaches. For more information on any of the following trials, click through to the clinicaltrials.gov webpage or call the trial coordinator listed below:

  • Genetically engineered T cells (“CAR T cells”) injected into the tumor or into the vein and designed to destroy breast cancer cells; Clinicaltrials.gov; Colleen Redlinger,  215-220-9693 (colleen.redlinger@uphs.upenn.edu)
  • DNA vaccine for high-risk patients in remission after adjuvant therapy; Colleen Redlinger,  215-220-9693 (colleen.redlinger@uphs.upenn.edu)
  • Specialized radiation therapy in combination with dual checkpoint blockade; Colleen Redlinger, 215-220-9693 (colleen.redlinger@uphs.upenn.edu)

More information on Drs. Vonderheide and Domchek's BCRF research can be read here

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