Matthew Herper posed a provocative question the other day while discussing CAR T technology: is this how we’ll cure cancer? (link).
Lets look at another example that promises to evoke the same question. Back in April, Steve Rosenberg gave a remarkable talk on the subject of patient-specific tumor-infiltrating-lymphocytes (TILs). We covered this talk in an earlier post (link). Today Dr Rosenberg further exemplified this personalized immunotherapy approach, via a case report in Science (link).
The patient had a highly metastasized gastrointestinal epithelial cell tumor called a cholangiocarcinoma. The patient had been through multiple rounds of chemotherapy, relapsed, and was enrolled in a clinical trial (NCT01174121). Lung metastases were isolated and subjected to whole exome sequencing. At the same time, these tumor samples were processed to derive TILs. The data from the sequencing identified multiple gene (and therefore proteins) that were mutated, and and expression constructs were used to determine if any of the mutated proteins were recognized by the TILs, which would proliferate when stimulated by interaction with antigen. Remarkably, a peptide fragment of the mutated ERRB2IP protein stimulated CD4+ Th1-type T cells in a HLA-restricted manner. These T cells were then expanded ex vivo.
The patient first received an expanded, activated TIL pool containing about 30% CD4+ T cells reactive to the mutated ERRB2IP protein. 40 Billion (yes, ‘B’) T cells were administered along with IL-2, a cytokine that keeps T cells alive and proliferating upon activation. The reactive TILs persisted for many months after administration and impacted the tumor, reducing tumor volume and inducing stable disease (a defined clinical endpoint). Ex vivo stimulation of recovered TILs demonstrated strong expression of the T cell activation receptors 4-1BB and OX40, and the secretion of the cytokines IFN-gamma, TNF and IL-2. The patient maintained tumor regression for 13 months, at which point metastases were observed in the lungs. A second infusion of activated TILs was given. In this case >95% of the TILs were reactive to the mutated ERB2IP protein. 10 Billion cells were administered. The patient then experienced a tumor regression that was maintain and progressive over time, up to and including 6 months post-administration (the last timepoint provided in the report).
This is an exciting step, moving immunotherapy into a class of tumors that are stubbornly resistant to many immunotherapeutic agents. A few interesting questions arise: 1) would induction of a CD8 response have an additive impact on the tumor? 2) would use of an agonist antibody to OX40 or 4-1BB synergize with this technique? 3) What was the immunosuppressive phenotype of the tumor and metastases, and could this information be exploited in the context of immune checkpoint blockade. 4) How often will metastases reflect the mutational landscape of the parental tumor (or other metastatic clones)? 5) Can the TIL technique be wedded to CAR T technology? I suppose there are many questions and issues.
This is a great next step in the rapid evolution of oncology treatment, and I’m looking forward to seeing much more.