Innovation in Oncology: The Synergy of New and Old Drugs

Some of the most important work in oncology today lies in combining multiple modalities to deliver on the promise of immune-oncology. The focus is often on immune checkpoint inhibitors, which can provide long-term benefits to some cancer patients, but any approach that targets a genetic biomarker generally only benefits the patients whose tumors have sufficient expression of that biomarker. No silver bullet exists for any cancer, and patients with higher mortality diseases such as ovarian cancer and non-small cell lung cancer often endure multiple rounds of therapy with decreasing clinical benefit. The question is how rational combinations of new and old therapies can increase the benefit for more patients, regardless of their biomarker status. Innovative work is now beginning to offer some answers. 

Engineering a better drug

When I was working on clinical programs to treat solid tumor indications over a decade ago, a lot of resources were being directed into research of CD19 and BCMA autologous CAR T-cell programs for patients with hematologic malignancies. As those now-common drugs were approved for commercial use, the question was whether it was possible to apply the learnings behind those drugs to develop treatments for solid tumor patients. Acknowledging the important biological differences and increased complexity of treating solid tumors, the potential still remained to apply the right engineering and develop a single highly engineered treatment that would make a difference for those patients. 

Years of joint industry-academic engineering suggest that highly engineered single agents will not be the most effective treatments for solid tumors; the solution will be combining the right drugs and administering them in the right way. Thus, international meetings that were once overwhelmingly focused on CAR T-cell therapies have evolved to discuss how to combine both autologous and allogeneic cell therapies with classic chemotherapeutic agents, radiation, and/or methods for stimulating the immune system. 

Delivering the combination “prime-boost” effect

Despite all the innovation in oncology, the primary initial treatment for solid tumors has remained platinum-based chemotherapy. Platinum is the most broadly utilized agent for solid tumors, and physicians rely on it to do a lot of the heavy lifting. Whether a patient’s tumor responds to platinum can be an important prognostic indicator of their tumor’s severity and aggressiveness. Some patients derive no benefit from initial platinum-based chemotherapy, while other patients respond initially but experience loss of effectiveness over time. Once a patient’s tumor becomes resistant to platinum, their doctor considers other anti-cancer agents, but those agents are generally less effective.

Because platinum-based chemotherapy remains a cornerstone in the treatment of solid tumors, an important goal in oncology drug development is overcoming platinum resistance. Mechanisms directed at augmenting platinum therapy itself have generally been ineffective. 

But what if a viral mechanism could be engineered to reignite patients’ depleted immune systems and resensitize them to platinum therapy, often described as the “prime-boost” phenomenon? The hypothesis is as follows: an oncolytic virus infects tumor tissue, where it preferentially replicates due to a rich supply of thymidine generally only seen in rapidly dividing cells. The host tumor cell lyses and releases additional viral particles and all the tumor antigens, triggering ignition of the innate and adaptive immune system. The patient’s immune system recognizes the newly inflamed tumor tissue, stimulating a new repertoire of T cells that deliver an anti-tumor response. The attack is then redoubled by the introduction of platinum therapy. Because the viral cycle delivers immunologic priming, the immune system is able to work with chemotherapy, delivering a profound and new anti-tumor effect. 

Exploring earlier use of combination therapies 

There is a lot of activity right now in identifying patients who are at high risk for recurrence of cancer. It may be possible to identify early signs of such high risk to potentially intervene early enough to prevent a patient’s cancer from progressing. For example, there may be a window of time where viral treatment may synergize with platinum chemotherapy in the earliest lines of treatment, when patients derive the most benefit from anti-cancer drugs. And the immunotherapeutic “prime-boost” effect has potential to help the growing number of patients who qualify for biomarker-directed therapy, as well as second-line therapies such as bispecific antibodies and antibody drug conjugates, which are used as monotherapy or in combination with platinum.

I’m optimistic about how artificial intelligence may contribute to some of the preclinical modeling, enabling companies to take the best shots at success as they invest their limited resources. Ultimately, when patients are getting the most difficult diagnosis of their lives or coping with diminishing efficacy of chemotherapy, more options for synergistic combinations of therapy are needed to improve their ability to fight their disease.

Photo: ST.art, Getty Images

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