Secondary Primary Cancer Prevention Strategies Following CAR T-Cell Therapy Are Underway

Manufacturing and bioengineering strategies for CAR T products as well as the identification of genetic safe harbors within the T-cell genome are crucial next steps to prevent secondary primary cancers (SPCs) from developing following CAR T-cell therapy, according to Shyam A. Patel, MD, PhD, and Saurabh Dahiya, MD, FACP. Additional prevention considerations include examining the prior therapies patients received before CAR T-cell therapy administration.

“The field of CAR T-cell therapy is expanding into non-cancer indications, and in those indications, specifically autoimmune [diseases], patients have had less exposure to prior genotoxic therapies such as chemotherapy or radiation therapy. As such, it would be a very important area/field to study to truly separate the risk of chemotherapy-related or genotoxic therapy-related injury to the DNA resulting in myeloid neoplasms [vs] the true effect of CAR T-cell therapy and CAR T-cell therapy–related inflammation in developing these secondary myeloid neoplasms,” Dahiya said in an interview with Patel and OncLive®.

In the interview, Patel and Dahiya discussed prevention strategies including the optimization of T-cell manufacturing and implementation of high-fidelity genomic testing, notably with baseline screening for clonal hematopoiesis. In a concurrent interview, the two highlighted aspects of the pathobiology of SPCs after CAR T-cell therapy and findings from their review as well as other studies examining these cancers. Patel is an associate professor at the UMass Chan Medical School in Worcester, Massachusetts, and Dahiya is an associate professor of medicine at Stanford University School of Medicine and Clinical Director of Cancer Cell Therapy in the Stanford BMT and Cell Therapy division in Palo Alto, California.

OncLive: What primary prevention mitigation strategies are important post–CAR T-cell therapy?

Patel: With regard to primary prevention in the field of cancer epidemiology, the main goal is to prevent SPCs from occurring in the first place. Primary prevention often begins with open ended conversations between physicians and patients about the real but very small risk for developing SPCs. Consent documentation should also include the risk for SPCs after administration of CAR T-cell therapies. Free flowing communication is also important between physicians and patients, and it can help patients make informed decisions about the treatments that they will receive; it may also help prevent SPCs from developing.

Another major aspect of primary prevention involves manufacturing considerations for CAR T products. Currently, CAR T products [can be] created after semirandom integration of a lentivirus into a T cell genome. This viral transduction is somewhat imprecise, and it can potentially lead to insertional mutagenesis. To better improve this process, one method of primary prevention from the manufacturing standpoint may be to establish methods for locus-specific integration [of transgenes]. One possibility for that could be the use of the CRISPR-Cas9 system to knock in CAR cassettes into certain areas within the T cell genome and base editing may also help with this.

Dahiya: To build upon what you said about the targeted insertion of the transgene, that area needs to be studied and developed. Bioengineering strategies need to be developed to insert the transgene into the genomic safe harbors, where the risk of insertional mutagenesis would be negligible. That’s an active area of research and bioengineering, and there will be more to come.

In terms of the secondary myeloid neoplasms or therapy-related neoplasms, a lot of them are probably related to the prior therapies that the patients [received]. Generally, most patients who get CAR T-cell therapy have received a lot of therapy beforehand, be it several lines of alkylating chemotherapy, high-dose chemotherapy, autologous transplant, long-term maintenance with immunomodulatory drugs, and other genotoxic therapies such as radiation. There is a lot of learning that needs to be gained as we move CAR T-cell therapy into earlier lines.

In the next few years, [we will] have a lot more data about the incidence of these SPCs as we move CAR T-cell therapy into earlier lines and as we [use and investigate] CAR T-cell therapy for autoimmune [diseases]. A lot of things in terms of the risk of developing these second myeloid neoplasms or myeloid neoplasms will be demystified and attribution that is directly related to CAR T-cell therapy will be further established as we move CAR T-cell therapy into earlier lines and compare data from fields such as autoimmunity.

What secondary prevention strategies can be implemented to monitor and mitigate the risks of SPCs in those receiving CAR T products?

Patel: Secondary prevention is also very important for risk mitigation, and one of the components of secondary prevention is identifying patients who have an inherent baseline risk or predisposition to developing SPCs. This may include patients with preexisting clonal hematopoiesis, in which there are somatic mutations within one’s own hematopoietic compartment; these patients may be at risk for clonal expansion of these mutated cells in the post–CAR T-[cell therapy] setting. It may be worth screening patients for baseline clonal hematopoiesis prior to administration of CAR T-cell therapy. Though, currently, there is no consensus [in] guidelines for this method of secondary prevention. Another major aspect of secondary prevention includes identifying patients who may have baseline inflammation or comorbidities that might place them at higher risk for developing SPCs.

Dahiya: Understanding what the right screening strategies are in these patient populations, specifically in the context of myeloid neoplasms, is [key] too. The data are evolving on the role of clonal hematopoiesis and clonal hematopoiesis dynamics post–CAR T-cell therapy. It would be interesting to see if there’s a particular type of clonal hematopoiesis of indeterminate potential [CHIP] mutation that is seen [and] if those are the patients who are [at] the highest risk of developing myeloblasts. Also, if there’s an expansion in allele frequency of these certain CHIP mutations, are those patients at high risk? That research is ongoing and we’re following it very closely. Lastly, at a minimum, the recommendation would also be to have age-appropriate screening done for patients who get CAR T-cell therapy. There are no other screening strategies that we would recommend at this time but continuing with age-appropriate screening for recipients of CAR T-cell therapy [could be done].

How can education on risks of these SPCs linked with this modality be improved?

Patel: Education on risks for SPCs linked to CAR T-cell therapy begins with open communication between clinicians and patients about the risks. Prior to the administration of CAR T-cell therapies, physicians or clinicians should inform their patients about the small possibility of developing SPCs. We can improve education by informing our patients about this real risk, but also let them know that the risk is quite low, typically in the range of 4% or less. At the provider level, physicians can evaluate the primary literature and provide education to healthcare providers in this process of administering CAR T-cell therapies to patients.

Dahiya: Very well said Dr Patel. One thing to understand is about the competing risk from the primary malignancy itself and the intent to give the patient the best shot at cure. Currently, the competing risk from having an adverse effect or dying due to progression of disease is much higher than the risk of developing SPCs for most [patients] where there is CAR T-cell therapy that is indicated [as treatment]. The risk is very low. The risk [of developing] transgene-positive T-cell lymphoma is extremely rare; only a handful of patients have been reported to have that event. The risk of [developing] transgene-negative T-cell lymphoma is also extremely low and is lower or comparable with the general population’s risk of developing these malignancies. The risk [of developing a] myeloid neoplasm [or] solid tumor appears to be less than 4% to 5% which is on par with what is seen with other alkylating chemotherapies or high-dose chemotherapy strategies that are often deployed in the treatment of hematologic malignancies.

At this time, the main message is [that] the risk of these secondary primary malignancies is rather low and [CAR T-cell therapies] still remain very efficacious treatments—often in certain cancers such as large B-cell lymphoma, [they] provide the best shot at cure.

How can interdisciplinary collaboration be enhanced to address the risk of these SPCs?

Patel: Interdisciplinary communication can be enhanced by ensuring that all parties are educated about the objective data behind the risk for SPCs following CAR T-cell therapy. Currently there are there is some misinformation about the risk for SPCs, and thus far, a causal relationship has not really been proven. Primary care physicians and oncology professionals should work with centers of excellence in understanding the risks and establishing good follow-up care plans for these patients.

Reference

Patel SA, Spiegel JY, Dahiya S. Second primary cancer after chimeric antigen receptor-T-cell therapy: a review. JAMA Oncol. Published online December 12, 2024. doi:10.1001/jamaoncol.2024.5412