A new age of theranostics – Transforming the immuno-oncology landscape
At the 2015 American Association of Cancer Research (AACR) annual conference in Philadelphia, April 18-22, plenary sessions, posters and abstracts were again abuzz with the ability of monotherapy and combination drugs to amplify and expand T cell responses and ultimately kill cancer cells. From standard of care chemotherapy and radiotherapy to new immuomodulatory drugs in pre-clinical and clinical development, these novel treatments showed that there is an urgent need for a new class of immune molecular diagnostics to better stratify and predict a patient’s response to different therapeutic modalities, as well as to identify early markers of cancer recurrence.
Enter Adaptive Biotechnologies’ immunoSEQTM Assay. immunoSEQ combines the capabilities of multiplex PCR with high-throughput sequencing and sophisticated bioinformatics to profile T cell (and B cell) receptor (TCR) repertoires. Adaptive is validating immunoSEQ as a novel oncology diagnostic to accurately and reliably quantify the density and clonality of tumor infiltrating lymphocytes (TILs) to assess disease prognosis and response to therapy.
Karsten Pilones, of Sandra Demaria’s lab at New York University (NYU), presented preclinical data comparing ipilimumab (Yervoy, BMS) and radiotherapy as monotherapy and in combination in the 4T1 mouse breast tumor model, which is characterized by aggressive metastases to the lung. Using the immunoSEQ Assay, the group was able to show dramatic clonal expansion with the combination of ipilimumab and radiotherapy, which was characterized by the emergence of several unique clones not seen in either of the monotherapy treatments. The authors conclude that while radiotherapy promoted T-cell priming and broadening of the repertoire, CTLA-4 blockade significantly expands the most frequent clonotypes. The combination has favorable, unique and synergistic effects.
These results have also begun to translate into the clinic. Encouse Golden, also working with Sandra Demaria and Silvia Formenti at NYU, presented preliminary results from a prospective non-small cell lung cancer (NSCLC) study (NYU S14-00208). While it is known that metastatic NSCLC patients only marginally respond to CTLA-4 blockade, the combination of ipilimumab and radiotherapy led to objective responses in this study. These results are quite promising in the aggressive setting of metastatic NSCLC where the median overall survival is a mere 7 months. This study is continuing accrual of 29 patients. It will be interesting to apply immunosequencing in this clinical setting to assess T-cell infiltration and clonality in patients responding to the combination.
It will be also very interesting to incorporate immunoSEQ retrospectively in the analysis of pre-treatment, on-treatment and post-treatments samples from the phase III KEYNOTE-006, the first clinical trial that compares head-to-head two immune checkpoint inhibitors as front-line therapy for melanoma. The study was led by Antoni Ribas at the University of California Los Angeles (UCLA), who is a member of Adaptive’s recently formed Immuno-Oncology Scientific Advisory Board. KEYNOTE-006 showed impressive superiority of pembrolizumab (Keytruda, Merck) versus ipilimumab as first-line therapy for patients with advanced melanoma. Ipilimumab is currently the standard of care for first-line therapy for patients with metastatic melanoma, and pembrolizumab is approved as second-line therapy for patients with metastatic melanoma whose tumors no longer respond to ipilimumab or BRAF inhibitors. In this 834 patient study, pembrolizumab demonstrated superiority over ipiliumab across all endpoints including prolonged PFS (46.4% vs. 26.5%) and OS (87.6% vs. 74.6%), as well as a favorable safety profile compared with ipilimumab.
In another effort to “upfront” anti-PD-1 therapy, Edward B. Garon at UCLA presented data from another pembrolizumab clinical trial, the phase I KEYNOTE-001, focusing on the safety and efficacy of pembrolizumab in non-small cell lung cancer (NSCLC). In this study, the median duration of response exceeded a year among responders regardless of the degree of PD-L1 expression. The overall response rate for the entire 495 patients was 19%. However, 25% of screened patients had PD-L1 expression in at least half of their tumor cells. Among these patients, the overall response rate was nearly 50%.
Recent studies of melanoma response to immune checkpoint blockade show that expression of PD-L1 by tumor cells, immune cell infiltrates (CD8+ T-cells), and clonal T cell response all correlate with response to anti PD1/PD-L1 therapy. Potentially, clonal T cell response could be measured in a peripheral blood sample, but the extent to which these variables correlate in lung cancer is currently unknown.
Following these results, Merck submitted this data to the U. S. Food and Drug Administration (FDA) for review. BMS’s own anti-PD-1, Opdivo (nivolumab) was FDA approved on March 5, 2015 as the first immunotherapy drug in lung cancer. The potential addition of pembrolizumab to the NSCLC treatment armamentarium will be a welcome addition to the available treatment options in this setting.
While immune checkpoint blockade therapy represents an important advance in lung cancer treatment, only about 15 to 20% of NSCLC patients respond. Here is yet another opportunity to accurately correlate immune cell infiltration and T-cell clonality with response to anti-PD-1/PD-L1 therapy, particularly since PD-L1 expression alone does not always correlate with a patient’s true lung cancer histology.
AACR also highlighted the emerging convergence of immunotherapy and personalized medicine. Numerous studies are incorporating whole-exome sequencing to assess genomic determinants of response to immunotherapies. Indeed, the efficacy of anti-PD-1 was correlated recently with higher neoantigen burden and DNA repair pathway mutations, possibly enhancing neoantigen-specific T cell reactivity. The ability of a cancer’s genomic landscape to shape a patient’s response to cancer immunotherapies is further being explored in the engineering of novel T cell therapies. Philip Greenberg at the Fred Hutchinson Cancer Research Center reported relative long-term remissions in poor prognosis leukemia patients treated with WT1-specific CD8 T cell clones that were isolated and expanded in vitro from donor hematopoietic cell transfer. To improve on these results, Greenberg’s group genetically engineered a high affinity, WT1-specific, HLA-A2-restricted T cell receptor (TCR) that is introduced into patient CD8 T cells, and the transduced cells are infused into leukemia patients. Preliminary clinical trial results indicate anti-leukemic activity and persistence of transferred T-cells. The same TCR will also be tested soon in NSCLC patients and potentially other tumor types where WT1 is known to be commonly overexpressed. Similarly, a genetically engineered HLA-A0201 restricted and affinity enhanced tumor-specific TCR recognizing NY-ESO-1/LAGE-1 peptides (NY-ESOc259-T) was studied in a phase I/II clinical trial in multiple myeloma patients. Results showed T cell expansion and durable persistence. In contrast, relapse was correlated with a loss of NY-ESOc259-T persistence or tumor antigen escape.
Because of inherently different mechanisms of action and potential non-overlapping toxicities of T cell therapies and immune checkpoint inhibitors, a combination of these two therapeutic modalities may show promising results. This combination could enable T cell therapy persistence, further prolong responses and ensure immunotherapeutic suppression of T-cell exhaustion markers, such as PD-1, LAG-3 and TIM-3.
Indeed, we have come a long way since March 25, 2011, when the FDA approved ipilimumab injection for the treatment of unresectable or metastatic melanoma. Since then, the ability of immune checkpoint inhibitors to unleash a patient’s own T cells to efficiently kill tumors has revolutionized cancer treatment across tumor types. More than a dozen different immunotherapy agents are now approved, with the majority over the last decade,.
Looking ahead, as additional immunomodulatory therapies are approved either as single agents or in combination, the opportunity to incorporate in clinical practice reliable immune molecular diagnostics like the immunoSEQ Assay will be critical to identify patients with a higher likelihood to respond and to better monitor for potential risks of recurrence early. Adaptive is developing immunoSEQ as a potential prognostic and predictive diagnostic test with applications in a range of novel immunotherapeutics.
 Pilones K., et. al. (2015) AACR Abstract Number 2856.
 Golden E.B., et. al. (2015) AACR Abstract Number 244.
 Ribas, A., et. al. (2015) AACR Abstract Number CT101.
 Garon, E., et. al. (2015) AACR Abstract Number CT104.
 Rizvi, N.A., et. al. (2015). Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science, 348 (6230), 124-128.
 Greenberg, P., et. al. (2015) AACR Abstract Number SY31-03.
 Rapoport, A., et. al. (2015) AACR Abstract Number 4701.
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 Rosenberg, S., (2014). Decade in review—cancer immunotherapy: Entering the mainstream of cancer treatment. Nature Reviews Clin. Onc. 11, 630–632.