The Janssen Pharmaceutical Companies of Johnson

John Loffredo

Immunotherapy Data Advisor

Could you please walk me through your current role and responsibility?

As a Scientific Director in Oncology at The Janssen Pharmaceutical Companies of Johnson & Johnson, I lead the immuno-oncology translational research. I am responsible for support clinical development of prostate cancer therapies and evaluating assets in the portfolio of biomarker and precision medicine.

At Janssen, our team focuses on treatment for cure of cancer utilizing immune system. We are working on the novel intervention, autologous cell therapy, derived from induced potent stem cells (IPSC). Our idea is to convert these IPSC into immune cells that can fight cancer by engineering them ex vivo, outside of the body. This is incredibly significant as these stem cells grow perpetually in culture becoming a great source of cells for treating a wide array of patients. Currently, we work on the progress of this project targeting IPSC and also a couple of different targets.

What would you say are some of the challenges you have witnessed in the cancer immunotherapy space and how do you align yourselves accordingly?

In immunotherapies, we have two biggest pain points. One is translating preclinical data into clinical data. The other challenge is to predict what drugs will work in patients and what will not in tumor therapies.

For instance, we have been developing a potential cancer immunotherapeutic target, lymphocyte activation gene-3 (LAG-3), for its negative regulatory role on T cells, since 2005. Recently, we observed that our combination of anti-LAG-3 and anti-PD-1, doubled progression free survival in melanoma patients in the first line of treatment itself.

Contrary to this, we also have a fair amount of false predictions and target failures that didn't work in larger trials of immunotherapy. Take for example, T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is recognized as a promising novel target for cancer immunotherapy. A lot of pre-clinical data and some randomized patient data suggest that anti-TIGIT and anti-PD-L1 can help treat lung cancer, but a recent phase three trial reported it as negative.

We also have instances where our targets attain positive outcomes as well as the negative. Our Janssen team is trying to figure out the potent combinations that push on the gas in tumor patients. We just don't work on the potent blocking immune checkpoints, but molecules that activate the immune system as well. Our scientific team targeted CD3-bispecific antibodies directly activates the soldier T-cells of the immune system, recognizes and kills tumor cells. These transformative drugs are proven to work against plasma cell cancer, multiple myeloma and heme malignancy, lymphoma, achieving objective responses and tumor shrinks. However, we found that CD3-bispecifics have not worked well against solid tumors in prostate cancers. Therefore, we are trying to take other molecules such as CD-28 and 4-1BB, and add them to the T cell drugs to achieve better responses.

Would you like to share about the project initiative that you're currently working on cancer immunotherapy, leveraging the latest technological elements to make it successful?

In line with unique IPSC derived cell therapies, we are counting on making bispecifics work well and also the next generation of cancer vaccines. Certain cancer vaccines have been seen a mediocre success around, like Provenge, a prostrate cancer vaccine. It was pretty exciting when it was first approved, whereas now, the vaccine is quite occasionally used. Our Janssen group is focusing on leveraging advanced computer science and algorithms to pick out better targets in cancers and work on them.

We are well acquainted with the right usage of vaccines. In general, Covid-19 vaccination has Moderna as a prime vaccine differing in its intended function from the Pfizer boost or other combination of doses. Similarly, our vaccine strategies for cancers involve new targets using two different vaccines, one for the primer and another for the booster. We hope to bring these highly invaluable essentials in the clinic in coming times.

How do you envision the future of cancer immunotherapy?

Cell therapies continue to be at the very center of immunotherapeutic innovations. Some of the autologous cell therapies show optimistic signs of treating hematologic malignancies using the patient's own cells. Even one of these drugs of ours is recently approved. We are looking to enhance its expression against solid tumors, developing a drug for prostrate cancer undergoing phase one clinical trial. Over the next five years, cell therapies would emerge as an exciting space with profound drugs for solid tumors.

In other aspects, few of our target immune checkpoints including CD3 or TIGIT are not helpful as we had hoped. This is because the tumor micro environment is complicated and it is vital to turn off the anti-tumor response. In effect, our Janssen Global team is investing efforts to understand the negative influences that make immune system less efficient to attack tumors and target those elements. We aim to target the negative populations—two types of suppressor cells, T-helper cells and regulatory T-cells, to generate a better anti-tumor response.

What would be the single piece of advice you could impart to an aspiring professional in your field?

The immuno-oncology space is actually fascinating though it's very complicated. Sometimes I find folks coming into the industry, looking at the animal data, getting impressed, and say that this is clearly going to work. From my personal experience at Janssen, I have seen many combinations of drugs that work really well in animal models and moderate in humans. The positive animal data, even the mechanistic data, is important which at times can be yield surprising human data. It can eventually go the opposite way as well. It is highly important to be clear that we examine data along all spectrums of development, from in vitro studies to animal studies, and early human studies. Having an open mind and looking at data across all those spaces is a key quality that everyone needs to develop.