Cancer Immunotherapy Month: Greater Understanding of Immune System Leads to Advanced Targeted Treatments

Cancer immunotherapy has dramatically changed the landscape of medical oncology by offering more tolerable and effective alternatives to chemotherapy, according to David L. Bartlett, MD. Over the past 10 years, immune checkpoint inhibitors (ICIs) were introduced and gradually became adopted, even as first-line treatment for some diseases.

While immunotherapies offer safe treatment options for many disease types compared with the toxicities of chemotherapies, they have their own unique types of toxicities that must be managed carefully in the real-world setting.

Research into prognostic biomarkers and combination therapies have improved the efficacy of immunotherapy, while alternative approaches that utilize the immune response to treat cancer such as monoclonal antibodies and cell therapies are showing promise. Focused study of immunotherapy for cancer has generated a greater understanding of the tumor microenvironment. This research is leading to more advanced cell therapies that can target tumor-specific antigens and formulate new therapies that can be tailored to multiple disease types effectively.

During an interview with Targeted Oncology^TM, Bartlett, chair of the Allegheny Health Network Cancer Institute in Pittsburgh, Pennsylvania, discussed the adoption of key immunotherapies and how exploration of the tumor microenvironment and immune environment is opening new approaches to treatment.

Targeted Oncology^TM: How has immunotherapy changed over the last 10 years?

BARTLETT: I think it is interesting to see how cancer immune therapy has evolved over the last 10 years. It's been quite dramatic. If you think about 10 years ago, we just had 1 agent, the anti-CTLA-4 agent [ipilimumab (Yervoy)], which had just been approved.¹ There was excitement around that as a new class of agents. But then if you look at what's happened since then, it's just been an explosion of immunotherapy agents that have been approved and changed the way we manage cancers: all of the anti­–PD-1 and anti–PD-L1 [agents], bispecific antibodies, and oncolytic viral therapies, and then finally, the cell therapies including CAR [chimeric antigen receptor] T-cell and tumor-infiltrating lymphocyte [TIL] therapies. So it's been this massive evolution around cancer treatment over the last 10 years. It's hard to imagine it's only been that long given how much we've learned about the immune system during that time.

What ongoing or published trials of immunotherapy do you think have been the most practice changing?

Over the years, there have been a lot of key trials that have transformed our thinking about immune therapy, from the first TIL trials that have demonstrated a cure rate between 10% and 20% in melanoma,² to the CAR T-cell trials which have shown cures in B-cell hematologic malignancies,^3-5 to the large, randomized trials showing the impact of anti–PD-1 and ICI therapy.

The evolution of those trials is to now look at combination therapies and finally, combining chemotherapy and immune therapy together, using immunotherapy in the adjuvant setting, and moving from third- and fourth-line therapies up to first-line therapies. So much has gone on in terms of the clinical trials in immune therapies.

My interest being in gastrointestinal [GI] cancers, we're finally seeing immune therapy play a role in many of the GI cancers, and those have been game changing. For instance, the trials looking at atezolizumab [Tecentriq] and bevacizumab [Avastin] in the hepatocellular cancer [HCC] inthe IMbrave [150 (NCT03434379)] study, microsatellite instability [MSI]-high colorectal cancers and using pembrolizumab [Keytruda] upfront in the KEYNOTE-177 study [NCT02563002], and frontline immune therapy or checkpoint inhibition for colon cancers. Then, finally, with gastric junction cancers and gastroesophageal cancers, [investigators looked] at the combination of pembrolizumab and chemotherapy in a large, randomized trial showing an advantage over chemotherapy alone.⁶

I think what we're what we're finally seeing is that the immune therapies that have been so effective in what we consider to be hot, inflamed tumors like melanoma, renal cell cancer, and lung cancer are now being moved into a GI space where we didn't really appreciate that before. This is just going to continue to evolve with all the thousands of studies that are out there now.

How have immunotherapies been adopted as standard of care or as frontline options?

I think the standard immune therapies have become standard of care for many different malignancies, and it's a matter of whether we're using them as first-line or we're using them as salvage therapy after the failure of standard chemotherapies. [Agents] like atezolizumab/bevacizumab are now a frontline therapy for HCC. It's so much better tolerated and more effective than the previous agents, and it's a game changer for that. I think, similarly, using immune therapy and ICIs as frontline for MSI-high tumors, regardless of the histology, in colon cancer or pancreas cancer as upfront therapy has also been a game changer.

Which newer targets do you feel like are important for upcoming immunotherapies?

There are so many targets. If you think about all the ICIs, there's dozens of checkpoints that have been identified, all of which may have an impact when inhibited. We now know how to inhibit those checkpoints using antibodies. There are dozens of targets that we can go after that [researchers] are looking into right now. And it's exciting that a LAG-3 inhibitor [relatlimab-rmbw; Opdualag] was just approved.⁷

So you can just see this continuing to evolve. [In] bispecific-antibody therapies, where you engage T cells, activate T cells, and put them in close proximity with tumor antigens, we've identified many tumor antigens that it could be effective for. So the sky's the limit there as well. I think, by the same token, as we learn more about CAR T-cell therapy and how to get cell therapy into solid tumors, the targets are infinite in terms of the neoantigens and tumor antigens that we can look at.

What should more community oncologist understand about treating patients with immunotherapy?

Immune therapy has a different set of complications and adverse events [AEs] that I think most physicians are becoming more and more familiar with. But each agent is going to have its own unique AE profile that's going to have to be kept in mind. I think the issue of autoimmunity that's being stimulated by these immune therapy agents provides a unique spectrum of toxicities that have to be kept into account, how we manage those toxicities through other immune suppressants and steroids, and what impact those will have on the cancer response. I think all we're still evolving in that understanding. But those are all things that have to be kept in mind as we're using these agents.

It's also important for everybody to keep up with what's being reported because thousands of clinical trials are active. We're constantly learning more, and more therapies are being approved, and that will continue to happen. So stay tuned, be aware, and become comfortable with the AE profiles of these unique agents and combinations of agents.

What upcoming research into immunotherapy is important to highlight?

I am very interested in cell therapy with TILs; expanding lymphocytes from the tumor microenvironment itself and in a variety of ways of activating those cells ex vivo and giving them back to patients. In our laboratory, we've been interested in developing what we consider a pre-TIL approach, where we use oncolytic viruses to transform the tumor microenvironment in a way that we can then harvest T cells that are very specific to tumor antigens, expand those T cells ex vivo and then give them back as a therapeutic agent.⁸

So it's about combining complex therapies—oncolytic viral therapy and T-cell therapy—through TILs to achieve a dramatic response. That all works very well in the laboratory. Now we're just looking at ways to bring that into the clinical realm. But I think it's just another example where we should be able to, through combinations and understanding the immune environments, enhance these immune therapy approaches. Treatments like that are agnostic to tumor type. In other words, it should work as well in colon cancer as it does in lung cancer or melanoma or sarcoma. I think that's where the future lies: all these different ways that we can manipulate the immune system and take advantage of the immune system to treat these cancers. I think this will continue to evolve for another couple of decades.

How can physicians support the progress of immunotherapy in clinical trials?

The key to all of the evolution of immune therapy is the engagement of all of our oncologists in the clinical trial process and working wherever you are to be able to get those clinical trials up and running and to accrue patients to those trials so that we can get these questions answered as quickly as possible. I would encourage everybody to work with their patients to understand how important these trials are and to continue to accrue to these trials.

_References:

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_{3. Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019;380(1):45-56. doi:10.1056/NEJMoa1804980}

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_{5. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852. doi:10.1016/S0140-6736(20)31366-0}

_{6. Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet. 2021;398(10302):759-771. doi:10.1016/S0140-6736(21)01234-4}

_{7. FDA approves Opdualag for unresectable or metastatic melanoma. FDA. Published March 18, 2022. Accessed June 8, 2022. https://bit.ly/3tp3YGR}

_{8. Giehl E,Kosaka H, Liu Z, et al. In vivo priming of peritoneal tumor-reactive lymphocytes with a potent oncolytic virus for adoptive cell therapy.Front Immunol. Published online February 18, 2021. doi:10.3389/fimmu.2021.610042}