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All About Immunotherapy with Dr Ramy Ibrahim

Dr Ramy Ibrahim 2.jpg

Salubris took the chance to speak to Dr Ramy Ibrahim from Parker Institute for Cancer Immunotherapy who was in town for the launch of the first Cancer Immunotherapy Consortium in Singapore.

Ramy Ibrahim, MD, Chief Medical Officer at Parker Institute for Cancer Immunotherapy, has been at the forefront of immunotherapy clinical development for more than 15 years. He helped develop some of the first breakthrough treatments in the field during at Bristol-Myers Squibb and MedImmune, now a part of AstraZeneca.

At Bristol-Myers Squibb, he helped shepherd ipilimumab from early phase II trials through regulatory approval of the first approved immune checkpoint inhibitor, Yervoy. He also played a key role in the early development of the anti-PD-1 drug nivolumab, as well as PD-L1 and CD137 antibodies.

At AstraZeneca, he directed teams working on durvalumab, an anti-PD-L1 antibody, and tremelimumab, an anti-CTLA-4 antibody, among others.

Q You're a respected leader in the field of cancer immunotherapy. How/why did you get into this area of focus years ago? Was it not exactly very exciting or widely accepted by the academic cancer community back then?

RI (Dr Ramy Ibrahim, MD): I started at the cancer vaccine branch at the National Cancer Institute (NCI) in the United States around 2001. It was a very different mood than today, when immunotherapy is seen as a very exciting area of research and therapeutic cancer vaccines are at the forefront of new research efforts.

At that time for vaccines, most of the work that we did showed negative results. We were doing vaccine studies, and none of them worked, and we did not know why they were not working.

Initially, when I was treating patients as an oncologist, I always looked at the immune system as something that prevents us from treating patients. Usually the reason that we stop giving chemotherapy to patients is when they develop a drop in their blood count. So as a medical oncologist, I did not like the immune system – because I thought, at that time, chemotherapy is the cure. I thought if we could just overcome the issues that we have with the immune system, we can actually treat patients.

But later at the NCI, that's when I started to really learn about and get interested in the value of the immune system, and how powerful it can be in fighting cancer. And that idea has just gotten stronger.

Q Can you talk a little about your early life – why did you study medicine? Did you consider other options before you went to medicine?

RI: I come from a family of physicians, and I was always very impressed with my parents when they were in their clinics, so it is something that I have always been passionate about. Oncology, specifically, is a challenge because I felt that for most other diseases, we had an option that we can offer to patients, whether it's hypertension or diabetes. But cancer was the one area where there was nothing that was working, and many patients were dying from this disease.

When I first started my fellowship, it was hard because I felt that I was not helping anyone. But it made me appreciate the importance of the quality of life, and anything that we can do to improve the quality of life of cancer patients is of a great value. It's not just about curing the patients from cancer, but really helping them have a good quality of life.

Eventually I came to feel that as great as improving quality of life is, we needed to start finding a cure. And that was why I started moving into drug development. I was really interested to find alternative therapies, novel therapy that we can offer to patients. And that is partly why I decided to come to the Parker Institute, because we are truly looking to help bring novel innovative treatments to patients faster.

Q What are some of the breakthrough treatments you have developed? How long did it take you to reach these breakthroughs?

RI: I was fortunate that the first drug I worked on was an immunotherapy drug, an anti-CTLA-4 antibody. Around 2006, we started to run clinical trials to understand if immunotherapy can be a replacement for chemotherapy, if we can combine anti-CTLA-4 antibody with chemotherapy for a better outcome.

The most challenging part was understanding the side effects. We started seeing side effects which are very different from the ones that we normally see with chemotherapy. So that was a lot of work done to try to understand them, ensuring that we control those side effects early on, and prevent them from having bad outcomes.

Q What are the worse side effects from immunotherapy treatment?

RI: Immunotherapy works by activating the immune system. Sometimes, instead of only targeting the cancer, the immune system can attack healthy cells. This can result in symptoms such as rashes or diarrhea, though side effects can vary depending on the treatment type.

For example, treatment with anti-CTLA-4 antibody can cause gastrointestinal issues, but the good news is it's manageable. Once we identify symptoms like diarrhoea, we intervene and reverse the inflammation with steroids, and it is usually very responsive to treatment.

However, several groups including the Parker Institute are actively working toward a better understanding of how checkpoint inhibitors and other immunotherapies, such as cell therapy, can affect other organs and cause other types of autoimmune disorders.

Q Immunotherapy vs Chemotherapy. There's much hype and debate over these two treatments. Tell us, is one better than the other, or are they complementary to each other in that both will have their roles depending on the cancer types?

RI: One of the things we have learned with immunotherapy is that we cannot generalize. We really need to start thinking about each patient individually, rather than how we have been doing it. For example, even within lung cancer, there are so many different sub-types of patients that would respond differently to different types of immunotherapies.

Immunotherapy as a class is a very broad term. We have cellular therapy, vaccines, checkpoints; there is a long list of immunotherapy and we cannot just put them in one bucket.

But to answer your question, I think immunotherapy and chemotherapy – and even radiation therapy, as well as other standards of care – can potentially be synergistic if we can identify the right type of chemotherapy with the right type of immunotherapy, at the right time.

Maybe we do not need the full dose of chemotherapy like what we are doing right now, because we will be using chemotherapy just to enhance the activity of immunotherapy.

Q It is often said that cancer immunotherapy is the beginning of a new era in the war against cancer. How so?

RI: Immunotherapy is now considered the fourth pillar in cancer therapy. For the longest time, it was surgery, radiation, and chemotherapy. And I think now, we can say that immunotherapy is an established pillar for cancer treatment. It is just the beginning, but what we have seen in the small sub-sets of patients who have benefited from immunotherapy is encouraging. Their responses are durable, we are seeing a very long-term effect, survival benefits, and many patients are tolerating the treatment well.

However, it is still a challenge because not everyone is having those sorts of responses. We are still having patients who are not responding to immunotherapy, so yes, it's the tail of the iceberg.

Q At what juncture would a doctor decide that immunotherapy should be stopped for a patient?

RI: We are still learning how best to give immunotherapy. Even with patients who are responding to the treatment, the question on how long do we need to keep them on immunotherapy remains to be an important question.

There are some research being done right now to understand this – do you need to give them one year of treatment and then monitor them to make sure it is not coming back, or do you give it until patients are not able to tolerate it? While I don't think we have a good answer, we always recommend keeping patients on treatment if they're tolerating it. We repeat the scans to ensure that it's not just the immune cells that are making the tumour appear bigger.

Q What do you think will be the next big immunotherapy breakthrough that we can look forward to?

RI: Cellular therapy is definitely a very promising approach. The successes that we have seen in liquid tumours or hematological malignancies are very encouraging, but we need to start thinking about solid tumours. Solid tumours are very different from liquid tumours. So I think the next big breakthrough would be whoever who can get cellular therapy to work in solid tumours.

Q What is the motivation behind all that you do? What do you like about your work?

RI: Seeing how the work we do affects the lives of thousands of patients is very rewarding. I don't see patients in the clinics now and I miss doing so, but when I see that we get a new drug approved, or when we get something that is very novel and cutting-edge made available to patients outside of clinical trials, it is no longer the few patients that I am helping. Now, there are thousands of patients, and sometimes, even millions of patients, who are benefitting from the work that we do. So for me, that is very rewarding. I love the fact that I am surrounded by very smart, dedicated and passionate scientists and researchers, and I always feel that passion is contagious. When you see the people around you working hard, you always feel that this is the motivation by itself.

Q Finally, what are your thoughts about the launch of the Singapore Society of Oncology-Cancer Immunotherapy Consortium? How critical is collaboration in the fight against cancer?

RI: At the Parker Institute, our model is really on supporting collaborations. We believe the only way for us to win the fight against cancer is by collaborations. We cannot continue working in silos and simply focus on our own research without looking at all the other efforts by other labs and clinicians. So I was very happy to hear of the launch of the cancer immunotherapy consortium in Singapore.