For decades, researchers have identified molecules that drive cancer progression, and these insights have led to new treatments. Targeted therapies, checkpoint inhibitors, and other approaches have critically expanded the anti-cancer toolbox.
However, strategies that work in one tumor type may fall short in others, and clinical benefit can be fleeting, as tumors develop escape mechanisms. Even as biopharma acquires greater insights into cancer, drugs that provide durable responses and minimal side effects remain elusive.
Cancers are complex diseases that demand a differentiated drug development process: identify high-impact targets, adopt a modality-agnostic mindset, and develop the most effective therapeutic candidates. By focusing on the target’s unique biology and mechanisms, we can develop promising drugs.
The massive unmet need
Researchers have produced a variety of novel anti-cancer therapies – many target specific growth pathways, while others seek to unleash the immune system.
These approaches have produced successes and failures. Targeted therapies often lose effectiveness over time. Immune checkpoint inhibitors benefit a relatively small number of patients. CAR-T immunotherapies can produce excellent responses in a limited number of cancers, but they are expensive and can cause severe side effects.
These qualified achievements have sensitized the industry to accept what cancer gives them. New therapies may only improve survival by a few months. In an environment where approximately 10% of drugs receive FDA approval, this may seem like a win – but is it?
Despite these challenges, our goal should be to develop transformational therapies that answer unmet needs and give patients the deep and durable therapeutic responses they deserve. The industry must do better.
A diversified pipeline to meet the need
Given this track record, how can companies develop drugs that dramatically improve patient outcomes? For Cullinan Oncology, the process starts with promising targets and continues through crafting novel, creative anti-cancer agents.
This approach has yielded a rich and diverse pipeline, including two T cell-engaging bispecific antibodies, a collagen-binding IL-2/IL-12 fusion protein, a B7-H4 x 4-1BB bispecific immune activator, and a monoclonal antibody that can preserve immune-stimulating signals.
Each agent is driven by unmet clinical need. In acute myeloid leukemia (AML), the five-year survival rate for people older than 20 is only 27%. Many patients endure intensive chemotherapy, as well as stem cell transplants, which are difficult to tolerate, especially for the elderly – the majority of AML patients.
Existing targeted therapies inhibit the tyrosine kinase receptor FLT3, which is often over-expressed in AML. However, these inhibitors only address patients with mutated FLT3, and escape mutations can nullify their benefit. While FLT3 is an excellent target for AML, inhibiting its kinase activity may be limiting.
The T cell–engaging bispecific antibody (CLN-049) does not inhibit FLT3 kinase. Rather, it uses FLT3 as a tether on AML cells to simultaneously bind and engage T cells. FLT3 becomes a handle to precisely recognize cancer cells and engage the immune system to destroy them.
On another oncology front, cytokine therapies have shown great promise, but adverse effects dim their prospects. The most active and synergistic cytokines, IL-2 and IL-12, produce systemic toxicities that limit their therapeutic potential. However, cytokines can potentially heat up immunogenically cold tumors, possibly making checkpoint inhibitors more effective.
CLN-617 is a pan-cancer agent that combines IL-2 and IL-12 into a single molecule. Designed for intratumoral injection, CLN-617 includes collagen-binding and size-enhancing domains that keep it inside tumors. This combination may reduce systemic toxicities, boost immunotherapeutic effectiveness, and generate systemic immune responses against distant, non-injected tumors.
Some B-cell non-Hodgkin’s lymphoma (B-NHL) subtypes are potentially curable, but many patients are still waiting for answers. CLN-978 is a human, T cell-engaging, bispecific antibody that potently binds to CD19 on malignant cells, CD3 on T cells, and human serum albumin to extend its serum half-life.
Preclinical studies have shown CLN-978 effectively targets B-NHL cells expressing very low CD19 levels, where current targeted therapies lose effectiveness.
CLN-418 is a bispecific antibody designed to produce robust, highly controlled, anti-cancer immune activation. It binds to B7-H4, a ligand in the PD-L1 family that is minimally expressed in healthy tissues and highly expressed in various tumors, and 4-1BB, a T cell costimulatory receptor that can dramatically stimulate T cells to kill tumor cells. By cross-linking B7-H4 and 4-1BB, CLN-418 has the potential to direct 4-1BB to tumors, possibly avoiding detrimental immune effects, such as liver toxicity.
Finally, CLN-619, a monoclonal antibody with possible pan-cancer applications, targets MICA/MICB. These proteins alert the immune system to cell damage and direct natural killer cells, and certain T cells, to clear them. However, cancers often evade this signaling mechanism by shedding MICA/MICB from tumor cell surfaces. CLN-619 prevents cancer cells from shedding their MICA/MICB extracellular domain, preserving the pathway and enabling immune recognition and tumor cell destruction.
Biopharma companies are sometimes wed to a single platform, but that can be limiting. Even when the approach is successful in one setting, there are no guarantees that success will translate to others.
While achieving FDA approval and clinical acceptance are worthy and challenging goals, they can obscure the need to strive for therapies that produce durable outcomes and tolerable experiences for patients. In other words, we shouldn’t be trying to move the needle, we should be adopting an entirely new scale.
Learn more about Cullinan Oncology and how a modality-agnostic approach advances a diverse pipeline.