Outsmarting Cancer: Next Generation Therapies

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Protein degradation, cell therapy, synergistic combinations and changes in personalized cancer therapies will drive the next generation of therapeutics, but not necessarily in the ways people might expect.

Personalized cancer therapy, for example, seems to be losing ground to other therapies simply because of logistics and finances. “Speed of manufacturing and the cost of getting the therapy to the patient are the challenges,” William Ho, CEO of In8bio, said during a live panel at Biotech Showcase during J.P. Morgan Week.

“At this point, personalized cancer therapies are used to treat fourth- and fifth-line refractory patients, but by the time a therapy is manufactured, many of those patients will have died. That may not be the case with earlier-stage patients.” As an added hurdle, “It’s difficult to control quality with point-of-care manufacturing.”

“The financial resources aren’t there for every patient to have personalized cancer therapy,” Kanya Rajangam, M.D., Ph.D., CMO of Nkarta Therapeutics, emphasized. That’s why Nkarta and others are focusing upon therapeutics for broader populations.

That realization is driving precision medicine, in which companies like Nkarta and I-Mab Biopharma identify genetic common denominators that can benefit broader populations and lower treatment costs.

Thoughts around combination therapies are changing, too. Part of the challenge with this approach lies in defining the term ‘effectiveness,’ Weimin Tang, chief business officer at I-Mab Biopharma said. “Is it defined as generating a signal (against a target) or improving outcome?”

Initially, researchers identified compounds with some degree of action against the target and combined them to create synergies. Now, in a stunning rethinking of the challenge, scientists are investigating compounds that have little or no effect as monotherapies but, when combined, generate promising signals.

Looking at a drug’s isolated effects and whether those activities are statistically significant “is an inefficient and unethical way to treat patients, particularly during a pandemic,” Spiro Rombotis, president & CEO of Cyclacel Pharmaceuticals, said. He advised determining whether it makes biological and medical sense to combine particular therapies, with the understanding that some therapeutics that do not work well alone will work in combination.

Treatments for big bulk tumors are an example.  As single monotherapies, few agents do much against big bulk solid tumors, he said. “Building upon their synergies, however, one plus one can equal five. There are ways to combine therapeutics to enhance synergy.”

Cell therapies also are emerging as potentially effective treatments, amidst the challenges of references that are framed in terms of complete response rates and durability of the therapeutic cell. Yet, complete response rates are irrelevant if the cancer cells weren’t completely obliterated, and durability doesn’t matter since treatments have evolved from autologous to allogeneic and are administered over time.

Therefore, Ho said his major benchmark “is when those who should be dead are still walking. Investors continue looking in terms of complete responses, but in cell therapy, I have a target and I either killed it or I didn’t. If I didn’t, it’s still growing.” The patient may still die without any prolongation of life. “We don’t want to win the battle but lose the war.”

In8bio is looking at gamma delta T cells to help solve that dilemma. “They’re unique and can be delivered allogeneically, and can distinguish between healthy cells and tumor cells,” Ho said. “We are seeing long-term responses beyond 17 and 20 months, depending on the program, and plan to announce data on our solid tumor program throughout the year.”

The challenge, Ho explained, is not to go head-to-head with chemotherapy or any other treatment, but to drive a deeper response. “If I eradicate the tumor, I don’t need persistence of the cell. Our goal is to add to the standard of care to eliminate the cancer stem cells that remain and that ultimately grow back.” Consequently, benchmarks for cell therapy should vary based upon the type of cancer, the trial population, the disease and patients’ prior treatments.

IO therapies also are looking at new targets. “There’s a whole field of proteins associated with the progression of cancer,” Rombotis pointed out, so protein degradation is garnering interest. Cyclacel, for example, is working to overcome cancer’s defenses by suppressing certain proteins, such as MCL,1 MYCN, MYC, MYB, BCL2A1 and MDM2. It expects to announce Phase I data from its oral, protein degradation program this year.

“There very likely will be dozens of companies this year announcing Phase I data from protein degradation programs,” he predicted. “The field of overcoming resistance is very hot.”

Despite these and other advancements, the overall pace of innovation has slowed and many me-too solutions are in development, panelists said. For example, more than 1,700 trials involving checkpoint inhibitors are active, enrolling by invitation, recruiting or not-yet recruiting, according to ClinicalTrials.gov.

From an investment perspective, “The world is simple,” moderator Kevin DeGeeter, managing director of healthcare research, at Oppenheimer & Co. Inc., concluded. “In a bull market, investors embrace long-term value. In dreadful markets like we have currently, investors have a hard time looking beyond their noses.”

Currently, “Investors are focused on narrow silos,” Ho added, “but the biology is so complex that many of the elements are interlinked.” The way to drive efficacy is to drive synergy through therapeutic combinations and new modalities to drive a broader response than existing therapeutics can deliver.”

The challenge for biotech companies, DeGeeter stressed, isn’t which therapy to develop, “but whether they can generate results in a timeframe that investors can understand. Asking them to wait three years for data is a tough ask.”

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