Clinical Updates: April 2022

Tumor Mutational Burden May Help Predict Immunotherapy Response in Metastatic NSCLC

Tumor mutational burden (TMB) was associated with immunotherapy response and survival outcomes in patients with metastatic non–small cell lung cancer (NSCLC), according to study findings published in Oncotarget.

Although immune checkpoint inhibitors have substantially improved clinical outcomes for some patients with metastatic NSCLC, determining which patients would most benefit from the drugs has generated inconsistent findings for biomarkers such as PD-L1.

“Improved patient selection would better identify patients who benefit from immunotherapy as well as spare patients predicted as nonresponders from needless toxicity and cost,” noted investigators.

TMB measured by comprehensive genomic profiling (CGP) has emerged as a potential biomarker to predict a tumor’s sensitivity to immuno-oncology agents in a variety of advanced cancers. Moreover, high TMB has consistently been associated with improved clinical benefit among patients receiving immunotherapy for NSCLC, said the study authors.

The investigators sought to further assess the association of TMB with treatment response and survival outcomes in patients with metastatic NSCLC. They conducted a real-world multisite study to evaluate clinical outcomes by TMB collected from tissue samples among patients with stage IV NSCLC between 2012 and 2019 who were treated with immunotherapy-containing regimens in the first-line setting and underwent CGP.

In the study, 667 patients with NSCLC at 9 US cancer centers were stratified by initial TMB mutations/megabase (mut/Mb) measures of greater than or equal to 10 mut/Mb (high; n = 272) and less than 10 mut/Mb (low; n = 395).
“The majority of patients received CGP from Foundation Medicine (64%), followed by Caris (20%), and OncoPlex (8%). Foundation Medicine was widely utilized by 6 (67%) of the participating cancer centers, while Caris was utilized by 2 (22%) institutions and all other testing platforms were utilized by a single institution,” added the investigators.

Compared with patients who had low TMB, those with high TMB were significantly associated with a positive smoking history (P < .01).

Furthermore, lower TMB was associated with ALK (P = .01) and EGFR (P < .01) alterations, whereas higher TMB was associated with TP53 (P < .01) alterations. Actionable genomic mutations that were not significantly associated with TMB included BRAF (P = .18), ROS1 (P = .24), and RET (P = .43).

Regarding patient outcomes, 67% and 68% of patients with TMB less than 10 and TMB of 10 or greater were alive at the end of follow-up, respectively. In conducting a subgroup analysis of patients who received TMB testing with products by Foundation Medicine or Caris Life Sciences products within 60 days of treatment initiation (n = 141), the investigators found a significant association for those with high TMB vs low TMB with overall survival (HR, 0.43; 95% CI, 0.21-0.88; P = .02) and progression-free survival (HR, 0.43; 95% CI, 0.21-0.85; P = .02).

“Based on the results in this study and prior research, TMB along with other biomarkers, such as PD-L1, may help identify patients more likely to benefit from first-line immunotherapy,” the authors concluded. “Prospective research is warranted to validate the predictive utility of this biomarker specifically in patients with low PD-L1 expression.” 

Reference
Willis C, Bauer H, Au TH, et al. Real-world survival analysis by tumor mutational burden in non–small cell lung cancer: a multisite US study. Oncotarget. 2022;13:257-270. doi:10.18632/oncotarget.28178

Natural Killer Cell–Based Immunotherapy: A Less Toxic Treatment for Leukemia?

Although chemotherapy and radiation have long been standard treatments for leukemia, immunotherapies have been increasingly researched and are considered promising options. A recent review assessed current research on natural killer (NK) cells, which serve as the first line of defense against cancer and play a key role in mitigating abnormal cell population growth. The review, published in Cancers, also explores the cells’ potential use in leukemia treatment. Authors are from the University of North Texas Health Science Center in Fort Worth and Baylor Scott and White Sports Therapy and Research at The STAR, Frisco, Texas.

Leukemia is a bone marrow and blood cancer characterized by irregular hematopoietic stem cell differentiation, with main subtypes including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL). NK cells play a key role in the recognition and cytolysis of abnormal and rapidly proliferating cell populations.

Traditional chemotherapy and radiation cause nonspecific cell destruction and increase patients’ susceptibility to infection, adverse effects, and immune cell inactivation. However, immunotherapies such as NK cell–based therapy are targeted and antigen specific, using the patient’s own immune system to fight cancer cell growth.

NK cells typically make up approximately 10% of lymphocytes circulating in the body, moving in a latent state until receptor-ligand interactions stimulate them. NK cells do not have cytotoxic properties when in contact with healthy host tissues or cells, but they release lytic granules or produce cytokine to destroy any virally infected or cancerous cells they encounter. Research has shown that leukemia results in a decrease in the number of active NK cells as well as in their cytotoxic and degranulation abilities.

Thus, NK cell–based immunotherapy aims to increase NK cell activation by blocking the inhibitory interactions that occur when these cells encounter healthy cells under normal conditions. This type of treatment also expands NK cell populations and enhances their overall function. NK cell–based immunotherapies being studied for leukemia treatment include the following:

• adoptive transfer
• monoclonal antibodies (mAbs)
• chimeric antigen receptor–NK cells (CAR-NKs)
• bispecific/trispecific killer engagers (BiKEs/TriKEs)

Current research on these therapies aims to induce complete remission in patients and minimize the adverse effects often associated with them.

Monoclonal antibodies. One of the most common forms of NK cell–based therapy are mAbs, which block specific biomarkers and increase antibody-dependent cellular cytotoxicity to boost NK cell function. Combination therapy with different types of cytokines is one potential method of increasing NK cell populations. A small phase 1 trial of NK cells combined with the mAb rituximab after chemotherapy produced a complete response in 7 of 9 patients.

Adoptive transfer. This method involves isolating NK cells from the peripheral blood, bone marrow, or umbilical cord of the patient (autologous) or a healthy donor (allogeneic) and purifying or genetically modifying the cells with cytokines before infusing them back into the patient. When the NK cells encounter incompatible ligands, graft-versus-leukemia can occur and increase their activity, killing leukemic cells. This has proved effective in AML especially, although relapse is common and posttransplant pharmacological intervention is a key aspect of success.

CAR-NK cell therapy. This treatment is in experimental phases, but it may be capable of killing cancer with minimal risk of toxicity or graft-vs-host disease (GVHD). This makes CAR-NK a potentially less toxic option than CAR T-cell therapies, which have shown success in refractory and relapsed B-cell ALL cancers but often cause neurotoxicity or cytokine release syndrome (CRS) and come with a higher risk of GVHD. CAR-NK also has the potential to be more accessible because it does not have to be individualized to each patient and can come in an off-the-shelf form.

BiKEs and TriKEs. These are engineered mAbs, created by fusing together single-chain variable fragments to make them bi- and trispecific for certain tumor antigens. NK cells can recognize the BiKEs or TriKEs, then induce apoptosis of their target. The study authors note that whereas BiKEs have shown some success in inducing antibody-dependent cellular cytotoxicity on target cells, TriKEs have shown superiority in inducing cytotoxicity, degranulation, and cytokine production.

Leukemia cells have been shown to be capable of manipulating expression of NK cell receptors to go unrecognized by NK cells, and targeting the biomarkers involved in this process could also be an avenue of treatment as these therapies are explored. Specifically, NK cell receptors 2B4, CS1, and LLT1 may be effective targets.

Continued research and more clinical trials are needed to determine the effectiveness of NK cell–based treatments, although there are some ongoing trials. Researching the specific receptor-ligand interactions that make NK cells cytotoxic in the presence of cancer cells may also aid in the understanding of these treatments, the authors noted.

Overall, the review authors see great potential in NK cells as future leukemia treatments are developed. “In addition to providing an alternative therapy for patients who may not respond to conventional treatment, NK cell immunotherapy focuses on harnessing a patient’s own immune system to fight cancer proliferation, minimizing off-target effects,” they wrote. 

Reference
Allison M, Mathews J, Gilliland T, Mathew SO. Natural killer cell–mediated immunotherapy for leukemia. Cancers (Basel). 2022;14(3):843. doi:10.3390/cancers14030843