As Boston’s weather has started its turn from the frigid darkness that is a northeast winter to the longer days and lighter conditions of spring, the city is brimming with all the hallmarks that make this season what it is. It’s impossible to not feel a sense of optimism this time of year, and I can’t help but be struck by undeniable parallelism of this same sense of optimism that’s been palpable in the biotech industry over the past couple months.

I don’t need you to remind you just how cold this most recent “biotech winter” was for many companies and investors. With painfully high levels of negative data read-outs and clinical setbacks, as well as company restructurings and underperformance, we saw negative sentiment persist throughout the sector. When you’re in a winter like that, it’s tempting to think you’ll never emerge. And yet, following a steady and growing drumbeat of M&A, positive data read-outs, and improving macroeconomic conditions, things finally started to thaw toward the end of 2023. You can feel that new life is starting to be breathed into the biotech sector.

While we’re seeing these green shoots start to poke through on a broader level, I’d like to hone in on one area that’s near to our hearts at HotSpot – immuno-oncology (I-O).

In contrast to recent enthusiasm for the clinical and commercial success of GLP1 analogs to address the obesity epidemic, immuno-oncology (I-O) has been on a steady downward trajectory. Instead of generating excitement and interest, the I-O space has instead been frought with disappointments and clinical setbacks.It’s been ten years since anti-PD-1 agents upended the oncology treatment landscape, transforming the treatment paradigm for cancer patients and in turn, generating substantial value for the companies that developed these drugs. With such dramatic success, it came as no surprise that industry dove headfirst into the I-O space, working to develop second-generation I-O therapeutics to address the substantial need that still persists for many cancer patients with a range of tumor types.

That is where the first snowflakes of a long “winter” in I-O therapeutic advancement started to fall. Despite lots of buzz across industry, the scientific community, and healthcare investors for a number of these second-generation agents, the vast majority came up short in critical ways:

  1. The majority of second-generation immune checkpoint inhibitors offer only a singular mechanistic solution for a highly complex, multi-factorial problem that likely requires a “poly-pharmacology” approach.
  2. The vast majority of efforts were unable to establish the critical connections between PK, target engagement, biological effects, and changes in tumor. These connections provide all-too-important ‘reasons to believe’ for further investment and movement into earlier lines of therapy.
  3. These agents largely lacked the ability, or even the potential, to demonstrate any single-agent clinical activity, defaulting instead to combinations with approved standard-of-care therapies that muddy the ability to detect the true effect of the novel agent.

With incomplete mechanistic rationale, datasets that didn’t draw clear lines between dose – PK/PD – activity, and no clear single agent clinical activity, it’s very difficult to see where value creation would emerge…. and usually it didn’t. As a class, novel I-Os have seen limited successes in only select patient populations since the likes of pembrolizumab and nivolumab stormed onto the scene.

However, despite this long winter, new approaches, ranging from CD3 bi-specifics, to cell therapies, to cancer vaccines, and more recent novel intracellular mechanisms have started to turn the tide.

Take Janux Therapeutics, a biotech focused on developing immunotherapies that generate tumor-specific immune responses to attack and kill tumors without destroying a patient’s healthy tissue. In February of this year, Janux shared an early look at the data they’ve generated for two programs, including emerging data from Phase 1 studies of their PSMA-directed, anti-CD3, and EGFR-directed, anti-CD3 T-cell engager antibodies. Janux reported signs of clear monotherapy activity, with promising efficacy in heavily pretreated, metastatic, castration-resistant prostate cancer with their PSMA-directed T-cell engager and an impressive confirmed partial response in a patient with non-small cell lung cancer with their EGFR-directed T-cell engager. While early, these data demonstrate clear promise to advance this modality.

The world of cell therapy is another that has driven forward the I-O landscape, a scientific approach that involves engineering T cells to drive anti-tumor immune responses when infused into patients. One such company, Arcellx, recently reported the continued long-term responses from a Phase 1 study of their lead CAR-T development candidate in multiple myeloma. The compelling data excited the industry, as well as drove pharma engagement through an expansion of their partnership with Kite Pharma (a Gilead Company).

Another promising approach to I-O is cancer vaccines. A notable late-stage therapeutic candidate is Moderna and Merck’s mRNA-4157, which is advancing through Phase 3 clinical development. This candidate leverages AI technology to sequence a patient’s tumor and healthy tissue and in turn harness this information to create a vaccine construct, which is designed to induce an immune response against tumor cells that harbor these biomarkers. The application of Moderna’s vaccine technology to cancers is yet another example of innovative approaches to I-O, with these data eagerly anticipated by the scientific community and industry, as well as health authorities who appear ready and willing to to engage with sponsors on this approach.

At HotSpot, we hope to be part of the new growth in I-O with our CBL-B inhibitor, which is currently progressing through Phase 1 dose-escalation. CBL-B is a target we selected because it has the potential to avoid the pitfalls that have plagued other drug candidates. Mechanistically, CBL-B serves as a master regulator of the immune system, and its inhibition offers a poly-pharmacology approach to enhance the activation of T and NK cells, drive a more robust and sustained anti-tumor immune response in the tumor micro-environment, and make tumor-killing immune cells less susceptible to inhibition. We’ve designed and are executing a Phase 1 study to draw clear connections between target engagement, biological effect, and clinical activity. And critically, this mechanism and study design will enable us to see signs of monotherapy activity. We’re encouraged by our early progress and are eagerly looking forward to sharing clinical data as our program advances.

All in all, while It’s early – these green shoots are still just shoots – emerging data and reinvigorated industry focus leads us to believe the hopes of next generation I-O is starting to become reality. Let’s hope that as we roll toward summer, that some of these green shoots continue to grow and ultimately blossom into a next generation I-O field.