Immunotherapy has revolutionized cancer treatment, yet its benefits remain limited to a select group of patients. Only about 20% of cancers demonstrate durable responses to immunotherapy, with significant variations in effectiveness across different tumor types.
Understanding Hot vs. Cold Tumors
The distinction between "hot" and "cold" tumors lies in their immune cell composition and microenvironment. According to Dr. Drew Pardoll of Johns Hopkins University, "A hot tumor has a lot of immune cells in it, and a cold tumor does not." Hot tumors typically contain higher numbers of lymphocytes, particularly T cells, and show increased PD-L1 expression and tumor mutational burden.
Cold tumors, in contrast, create what Dr. Michael Curran of MD Anderson Cancer Center describes as a "T-cell exclusionary bubble." These tumors establish complex barriers, including stromal obstacles and dense collagen matrices, effectively blocking immune cell entry and function.
Innovative Approaches to Converting Cold Tumors
Several promising strategies are emerging to transform cold tumors into hot ones:
Bispecific Antibodies
These engineered proteins are showing remarkable potential. The recent FDA approval of tarlatamab (Imdelltra) for small cell lung cancer demonstrates their effectiveness, achieving objective response rates exceeding 50% in some patient subgroups.
Engineered T-Cell Therapies
Adoptive cell transfer techniques are advancing rapidly. A collaborative effort between researchers and Immatics has developed a T-cell receptor-transduced product targeting PRAME in melanoma, achieving 50% response rates in treatment-resistant cases.
Breakthrough in Challenging Cancers
Pancreatic Cancer
Despite being considered an immune "desert," new approaches are showing promise. A pioneering technique combining neo-antigen vaccines with PD-(L)1 inhibitors and chemotherapy has demonstrated significant improvements in post-surgical outcomes. Patients responding to the vaccine showed dramatically reduced relapse rates in the first two years.
Antibody-Drug Conjugates (ADCs)
Combinations of ADCs with immunotherapy are yielding encouraging results in traditionally difficult-to-treat cancers. Notable success has been seen in advanced bladder cancer and lung cancer, with potential applications expanding to colorectal and breast cancers.
Future Directions
Research continues to evolve, with new approaches including immune checkpoint cytoreduction agents showing promise in clinical trials. These novel therapies are particularly exciting as they've demonstrated effectiveness in patients who previously failed PD-1 inhibitor treatment.
Dr. Curran's lab has developed a dual PD-L1/PD-L2 inhibitor that has shown encouraging results in depleting immune exclusion barriers. "For the 55% of patients who have cold tumors that don't have an approved immune checkpoint indication, this drug will be able to expand the range of patients who are eligible to get these kinds of benefits from immunotherapy," notes Dr. Curran.
