Clinical Updates: Fall 2022

Could Combining Use of BTK Inhibition, CAR T-Cell Therapy Yield Better Outcomes in MCL?

As chimeric antigen receptor (CAR) T-cell therapy and Bruton tyrosine kinase (BTK) inhibitors become cornerstones of treatment for advanced mantle cell lymphoma (MCL) in their own right, authors of an article in Current Oncology Reports say studies suggest the feasibility of combining the treatments for improved outcomes.

There are currently 3 approved BTK inhibitors in relapsed/refractory (R/R) MCL: first-generation ibrutinib (Imbruvica) and second-generation acalabrutinib (Calquence) and zanubrutinib (Brukinsa). In 2020, CAR T-cell therapy entered the MCL market with the approval of brexucabtagene autoleucel (Tecartus) in patients with R/R disease.

Although both categories have yielded impressive efficacy for some patients, there are a group of patients who don’t achieve sufficient outcomes, including those who discontinue ibrutinib due to treatment intolerance, develop resistance to BTK inhibitor treatment, and have short-lived responses to CAR T-cell therapy due to a variety of factors, including T-cell exhaustion.

“Evidence suggests that concomitant administration of BTKi and CAR T-cell therapy may provide a greater treatment benefit than either agent alone,” noted the authors. “In vitro analyses demonstrate that stimulation of CAR T-cells with a BTKi enhances the Th1 response and T-cell effector activity by increasing cytokine production and cytolytic activity. In addition, exposure to a BTKi increases T-cell expansion, viability, and engraftment.”

With the jury still out on whether sequential administration of BTK inhibitors and CAR T-cell therapy is more beneficial than concomitant use, the group outlined recommended scenarios each approach. For example, the researchers recommend CAR T-cell therapy be used ahead of BTK inhibition in BTK inhibitor–naïve patients with high-risk disease characteristics because they will likely not achieve durable responses to a BTK inhibitor. According to the researchers, in cases like this, a BTK inhibitor could be used as a bridge in patients who did not respond or who had a partial response to CAR T-cell treatment.

The researchers recommend use of a covalent BTK inhibitor, either as monotherapy or in combination with another treatment like venetoclax (Venclexta), in patients who don’t respond to or relapse following CAR T-cell treatment and have not previously received BTK inhibitor treatment.

Noncovalent BTK inhibitors are recommended, either alone or in combination with another treatment, in patients who have previously been treated with a covalent BTK inhibitor.

The authors explained that to date, there is no approved option for concomitant use of CAR T-cell therapy and a BTK inhibitor—leaving an absence of standardized guidelines for the treatment approach—although the approach may be feasible in patients who are naïve to both because a combination of the two may improve outcomes.

“Evidence supporting the use of concomitant BTKi and CAR T-cell therapy is mostly limited to studies in CLL, as patients with CLL typically have low rates of [complete response] with CAR T-cell therapy, likely due to CLL-induced T-cell dysfunction,” explained the researchers. “In vitro studies suggest that ibrutinib may enhance CAR T-cell expansion and increase cell viability as well as improve cell engraftment, tumor clearance, and survival. Stimulation of CAR T cells with ibrutinib or acalabrutinib enhanced CAR T-cell effector function; prolonged BTKi stimulation further increased cytokine production and Th1 differentiation.”

Drawing on the limited data available in CLL, the researchers suggest that a BTK inhibitor be used as bridging therapy and during lymphodepletion in preparation for CAR T-cell therapy. The group noted that using a BTK inhibitor directly following CAR T-cell therapy may lead to drug-drug interactions, off-target toxicity, and immunomodulatory effects. They added that although no published data have yet pointed to increased toxicity or reduced efficacy associated with concomitant use of a BTK inhibitor during lymphodepletion or immediately after CAR T-cell therapy, providers should closely monitor patients for related toxicities and other adverse events. 

Reference
Munoz JL, Wang Y, Jain P, Wang M. BTK inhibitors and CAR T-cell therapy in treating mantle cell lymphoma—finding a dancing partner. Curr Oncol Rep. 2022;24(10):1299-1311. doi:10.1007/s11912-022-01286-0


Identifying ASCT-Ineligible Patients Who Could Benefit From CAR T-Cell Treatment

Researchers of a new paper have characterized groups of patients with diffuse large B-cell lymphoma (DLBCL) who may benefit from chimeric antigen receptor (CAR) T-cell therapy despite not being eligible for autologous stem cell transplantation (ASCT), including older patients with more comorbidities.

Both ASCT and CAR T-cell therapy are intensive and potentially curative treatment options for patients with DLBCL. Due to a growing amount of real-world data, there have been suggestions that CAR T-cell therapy—currently approved for use after 2 lines of therapy in this setting—may be superior to ASCT in the second line for patients with relapsed or refractory disease. Data also suggest that the technology may be an option for patients who are not eligible for ASCT based on certain patient characteristics, prior treatments, stem cell availability, or tumor chemosensitivity.

“Real-world experience has shown that CAR T-cell therapy is feasible in patients who would not have been eligible for an ASCT. Thus, it is important to identify this ‘subtle but real’ population of patients who are ASCT ineligible but CAR T-cell eligible,” wrote the researchers. “This population of patients will be further defined as we get more experience with CAR T-cell therapy. In particular, it will be important to improve our knowledge regarding treatment-related morbidity and mortality and, if possible, to develop scores capable of predicting the risk of severe/lethal toxicities (acute and delayed) after CAR T cells.”

Their findings were published in the European Journal of Cancer.

Currently, 3 ongoing prospective trials—ALYCANTE (NCT04531046), TRANSCEND-PILOT-017006 (NCT03483103), and DALY 2-EU (NCT04844866)—are assessing CAR T-cell treatment in the second line for patients not eligible for ASCT. The researchers of the paper in European Journal of Cancer highlighted the importance of identifying such patients to promote optimal use of CAR T-cell treatments.

For example, ASCT is typically offered in younger patients with fewer comorbidities, whereas CAR T-cell treatment has emerged as a safe option in less fit patients and those who are older. Typically, patients older than 65 to 75 years and patients with intermediate performance status, mild organ dysfunction, or mild comorbidities are not eligible for transplant. However, real-world data have suggested that CAR T-cell therapy may be an option.

The group noted that although each institution has its own definition of eligibility for both treatment approaches, eligibility is typically more flexible for CAR T-cell treatment.

The researchers also cited prior treatment as a consideration. Although a patient who previously received ASCT would not be eligible for the procedure again, they would be eligible for CAR T-cell therapy.

Another example outlined by the researchers is in a case when stem cell collection was not successful, thus inhibiting the ability for a transplant but still allowing for feasible CAR T-cell treatment. According to the researchers, in these patients, there is a more than 95% success rate in leukapheresis and CAR T-cell manufacturing.

Chemosensitivity is also a consideration because patients who are refractory to salvage chemotherapy would not benefit from high-dose chemotherapy followed by ASCT. However, due to the unlikelihood of cross-resistance, immunotherapy treatment with CAR T cells would be viable. 

Reference
Vic S, Lemoine J, Armand P, Lemonnier F, Houot R. Transplant-ineligible but chimeric antigen receptor T-cells eligible: a real and relevant population. Eur J Cancer. 2022;175:246-253. doi:10.1016/j.ejca.2022.08.019


Are NK Cell–Based Treatments the Next Approach in Immuno-oncology?

Amid efforts to improve and expand the use of chimeric antigen receptor (CAR) T-cell therapy, researchers of a new study are outlining the potential of CAR natural killer (NK) cell–based treatment in oncology.

Highlighting NK cells ability to quickly destroy malignant cells without antigen specificity, the authors identified opportunities to use NK cells, particularly in cases when T cells are not effective.

“NK cells have been explored for adoptive immunotherapy in a number of different cancers, particularly in leukemia and lymphoma, given their recognized graft-vs-leukemia effect,” the researchers wrote. “The adoptive transfer of NK cells after ex vivo activation has been shown to be safe and well tolerated in lymphomas, breast and lung cancer, and metastatic renal cell carcinoma (RCC) patients. The adoptive transfer of nonmodified or genetically engineered NK cells could provide a more innovative therapeutic approach for cancer immunotherapy.”

Currently 23 trials are evaluating genetically engineered NK cells, most of which are exploring the use of NK-92–derived CAR NK cells for use in hematological malignancies and solid tumors. The researchers noted that CD16 is not present in NK-92 cells, limiting its use with monoclonal antibodies that rely on antibody-dependent cell cytotoxicity function.

Results from 2 trials of multiple myeloma and glioblastoma are anticipated.

CAR NK cell–based treatments offer several advantages over CAR T-cell therapies. CAR T transfer is limited to autologous T cells to prevent the risk of graft-vs-host disease (GVHD), whereas CAR NK cells can be transferred from both autologous and allogeneic sources. CAR T-cell therapies require high manufacturing costs, uncertainty of collecting enough cells, and time for generation and expansion. CAR NK-cell therapy, explained the researchers, offers an “off the shelf” approach. Notably, CAR NK-cell therapy carries a low risk of cytokine release syndrome—a well-known adverse effect of CAR T-cell therapy.

NK cells have also been explored as adoptive transfer therapy, from both autologous and allogeneic sources. Although autologous transfer is considered a safer choice due , to compatibility from use of the patient’s own cells, there is a reduced antitumor effect because of lower CD107a degranulation, tumor necrosis factor α, and interferon-γ production.

Although there have been attempts to improve antitumor effects by expanding NK cells for adoptive transfer in vivo, inefficient results have been seen in acute leukemias and in solid tumors, as the reinfused NK cells remaining in circulation have limited tumor-homing ability.

“Due to the suboptimal efficacy of autologous NK-cell infusions, allogeneic NK cells have been heavily assessed as a source for NK-cell adoptive transfer therapy. Allogeneic NK cells can be obtained from peripheral blood, umbilical cord blood, pluripotent stem cells, and commercially available NK cell lines such as NK-92,” the authors wrote. “They can provide an off-the-shelf option that can reduce manufacturing costs and dose escalation protocols and make reproducibility much easier.”

According to the researchers, allogeneic alloreactive NK cells offer a protective role against GVHD similar to that seen with CAR NK-cell therapy. The reason for this protective capacity, explained the group, is the ability of NK cells to work in a non–antigen-specific way and to regulate immune cells typically involved in the GVHD process. 

Reference
Mendoze-Valderrey A, Alvarez M, De Maria A, Margolin K, Melero I, Ascierto ML. Next generation immune-oncology strategies: unleashing NK cells activity. Cells. 2022;11(19):3147. doi:10.3390/cells11193147


Organ Transplant Patients at Higher Risk of BCC vs the General Population

Development and progression of basal cell carcinoma (BCC) were more common among organ transplant recipients (OTRs) compared with the general population, and the former also had a higher rate of deep invasion, according to new study findings published in Archives of Dermatological Research.

The study authors noted that their data point to immunosuppression as the culprit, which echoes previous research and highlights the greater skin cancer risk these patients face.

“The most frequently occurring skin cancers in OTRs are squamous cell carcinomas (SCCs), and because they are responsible for high morbidity and mortality, SCCs in OTRs have been studied extensively,” the investigators wrote. “BCCs occur less frequently than SCCs and rarely metastasize, and thus BCCs in OTRs have received relatively little attention despite their increased incidence compared with the general population.”

Data for their analysis were provided by histopathology reports from 2 prospective skin cancer studies, 1 among the general population (QSkin Sun and Health Study) and 1 among OTRs (Skin Tumors in Allograft Recipients). These data were on BCC tumor site, size, level of invasion, subtype, and biopsy procedure. Age- and sex-adjusted prevalence ratios were also examined.

Overall, prevalence results show an average of 3.51 cases of BCCs per OTR, or 702 BCCs from among 200 OTRs. This rate was significantly higher than the 2.15 BCC cases per general population, or 1725 BCCS seen in 804 cases.
Cases were more often seen among male patients in both groups, but men accounted for more of the OTRs vs general population cases: 76% vs 56%. In addition, among the OTR group, more than twice as many patients with BCC had their skin checked more than once each year: 53% vs 21%.

No matter the biopsy method—excision, punch/shave biopsy, or curettage, respectively—the head/neck region was the most common site for a BCC among both patient cohorts: 46.4% and 41.9% in the OTR group and 43.4% and 33.4% in the general population. Excision was the most common surgical method overall for tumors of 2 cm or smaller, but tumor size data were lacking from a sizeable portion of each group who had punch/shave biopsy or curettage: 75.5% of the OTR group and 67.1% of the general population group.

The authors noted this is because, “substantial proportions of BCC tumors in each group were diagnosed and treated only by partial biopsies, thus tumor size and depth of invasion were unknown for over two-thirds of partially excised BCCs in both case groups.”

There were also more instances of unknown tumor depth in the OTR group, but this group also had a higher rate of nonaggressive tumors for those who underwent excision vs the general population patients: 82.0% vs 68.6%, respectively. Nonaggressive rates were similar for punch/shave biopsy or curettage, at 83.1% and 83.2%, respectively. Aggressive tumor results were more often seen in the general patient excision cohort (31.4%) compared with the OTR excision cohort (18.1%).

A greater number of higher-risk BCCs per person were seen in the OTR group, among whom more tumors were larger and invaded skin beyond the dermis layer:

• Higher-risk BCCs were seen in 327 per 128 cases in the OTR group vs 703 per 457 cases in the general population group.
• Tumors 2 cm or larger were seen in 7% of the OTR group vs 4% in the general population group.
• Cancers invading beyond the dermis occurred in 5% of the OTR patients vs 2% of the general population group.

Adjusting for age and sex produced higher prevalence ratios for BCCs on the scalp or ear, higher-risk BCCs that were 2 cm or larger, and BCCs that extended beyond the dermis among the OTR group compared with the general population.

“This is among the largest clinicopathological series of BCCs in OTRs reported to date and one of the few to compare BCCs in OTRs and the general population,” the authors concluded. “Patient care and future research to confirm these findings may both benefit from enhanced communication between treating clinicians and dermatopathologists not only via the pathology requisition but also by comprehensive histopathologic reporting of BCCs.”

Reference
Pandeya N, Huang N, Jiyad Z, et al. Basal cell carcinomas in organ transplant recipients versus the general population: clinicopathologic study. Arch Dermatol Res. Published online October 25, 2022. doi:10.1007/s00403-022-02403-6.

Review Finds Dermoscopy Can Reduce Incomplete Excision of Skin Cancer

Use of dermoscopy, which uses a handheld light to examine cutaneous lesions prior to surgery for skin cancer, reduces the likelihood of cancer remaining in surgical margins following excision, according to a recent review of 6 studies involving 592 patients.

The review, which appeared in the Journal of Clinical and Aesthetic Dermatology, examined what the authors called a “relatively inexpensive and readily available” tool to reduce rates of incomplete excision. The authors, from the Department of Plastic and Reconstructive Surgery at Hull University Teaching Hospitals in the United Kingdom, noted that most surgeons in skin cancer clinics would be familiar with the method.

“However,” they wrote, “the quality of the available evidence is low and at significant risk of bias, and therefore further research is required in this area.”

Authors screened 452 studies for eligibility for their study and found 6 that met criteria of the review, which sought to examine whether the use of dermoscopy as an adjunct to clinical examination could improve rates of incomplete excision in nonmelanoma skin cancer lesions.

The authors noted as limitations that the overall number of available studies was small and that 3 of the studies selected were performed by the same team. There were 5 studies involving patients with basal cell carcinomas
(498 patients) and 1 study with patients who had squamous cell carcinomas
(94 patients).

The odds ratio of incomplete excision when guided by dermoscopy was 0.29 (95% CI, 0.25-0.34). Heterogeneity was assessed, and the I2 statistic was found to be 0%. Of note, all 6 studies found that dermoscopy improved the likelihood of complete excision.

To the authors’ knowledge, “this is the first systematic review that has focused on the comparison of dermoscopy as an intervention in marking of surgical margins to determine the primary outcome of incomplete excision rate.”

Nonmelanoma skin cancers removed with surgery are typically on the head and neck due to UV light exposure, and incomplete excision rates have been reported to be 10% to 17%, the authors noted, with higher rates for periorbital excisions.

There are many risks with incomplete excision, including recurrence requiring additional treatment. “In cosmetically sensitive areas, the aesthetic outcome sometimes overshadows the aim of oncological clearance, and so as little tissue is removed as possible to minimize the defect size though compromising on the oncological margin,” the authors wrote.

Despite the low cost and availability of dermoscopy, the authors noted that training is limited outside the field of dermatology. With more patients likely to present with skin lesions, however, the authors recommended that more physicians be trained in dermoscopy, especially surgeons.

“We would recommend that dermatoscopes be routinely available and used in operating departments, that training in their use be provided for surgeons, and that measurement of excision margins, along with the use or otherwise of dermoscopy, be recorded to aid future analysis of the utility of dermoscopy,” they wrote. 

Reference
Hurley AR, Totty JP, Pinder RM. Dermoscopy as an adjunct to surgical excision of nonmelanoma skin lesions: a systematic review and meta-analysis. J Clin Aesthet Dermatol. 2022;15(9):45-49.