Efficacy, Toxicity and Targets for Adoptive Cellular Therapy in Multiple Myeloma: A Systematic Review
Authors: Usman Muhammad , Tariq Muhammad Junaid , Ijaz Awais , Fraz Muhammad Asad , Khan Ali Younas , Nunes Cavalcante Parr Nadia Carenina , Khalil Muhammad Jahanzeb , Asghar Arveen , Durer Seren , Durer Ceren , Ahmad Malik Qistas , Sohail Chaudhry Saad , Malik Mustafa Nadeem , Anwer Faiz 
Published: October 2019

Abstract
Introduction
Advancement in multiple myeloma (MM) has led to the development of adoptive cell transfer (ACT), an immunotherapeutic modality that utilizes body's own effector cells (T cells or Natural killer cells) to kill cancer cells. These include chimeric antigen receptor T cells (CAR-T cells), genetically modified T cell receptors (TCRs), activated Natural Killer (NK) cells and native T cells armed with bispecific antibodies. Potential antigen targets for TCRs in MM include B cell maturation antigen (BCMA), CD19, CD138, NKG2D, Ig kappa, LeY and SLMF7/CS-1, MAGE A3 and NY-ESO-1. The purpose of this review is to summarize various types of cellular therapies which are being tested in early phase clinical trials for treatment of MM.
Methods
We performed a comprehensive literature search (PubMed, EMBASE, AdisInsight and Clinicaltrials.gov) between January 2008 to December 2017, to identify early phase (I and I/II) trials of cellular therapy for the treatment of MM. We included studies involving cellular therapy, irrespective of the geo-location, age, sex or specific eligibility criteria.
Results
With initial search yielded 2537 phase I and phase I/II studies. After initial screening by two reviewers and categorization by mechanism of action, 37 clinical trials (CTs) that involved ACT were included. Out of the 37 trials, 18 are active or completed (Table 1) and 19 are recruiting subjects (Table 2). Most explored mechanism of action (21 CTs) in these trials is CAR T-cell therapy directed against B cell maturation antigen (BCMA).
Anti-BCMA CART has shown promising efficacy of up to 100% objective response (OR) in a phase I trial (NCT03090659, n=22). In a phase I/II trial by Fan et al. (n=19), 6 (32%) patients showed complete response (CR), 12 (63%) developed near complete response (nCR), 1 (5%) achieved partial response (PR). In phase I trial by Ali et al. (2016, n=12), anti-BCMA CART cells led to stringent complete response (sCR) in 1 (8%) patient, very good partial response (VGPR) in 2 (16%), PR in 1 (8%) and stable disease (SD) in 8 (66%). Grade 3-4 cytokine release syndrome (CRS) was reported in 3 (25%) patients receiving high dose of CAR T cells (9 x 106 / kg in 2 patients and 3 x 106 /kg in 1 patient). Cohen et al., 2017 (n= 24) reported the objective response rate (ORR) defined as ≥PR in 11 (47%) patients. In 75% of patients with grade 3-4 CRS, tocilizumab/siltuximab was used to manage CRS.
According to Garfall et al. (2018, n=10), administration of anti-CD19 CART after autologus stem cell transplant (auto-SCT) improved progression free survival (PFS) in 2 (20%) patients compared to PFS due to auto-SCT done earlier in same patients (from 181 to 479 days and 127 to 249 days).
Leivas et al. (2016, n=5) showed that infusion of expanded and activated natural killer cells (NKAE) with lenalidomide have shown better response (PR=1, SD=1, SD to PD=1) than NKAE with bortezomib (SD=1, PD=1). In 10 (83%) patients, VGPR or better response was achieved after infusion of allogenic cord blood derived NK cells along with auto-SCT (Shah et al., 2017).
Rapoport et al. (2017, n=25) infused CAR T-cells against cancer testes antigens (NY-ESO-1, LAGE-1a) and demonstrated the OR in 19 (76%) patients (1 sCR, 12 VGPR, 6PR) at day 100.
Al-Kadhimi et al. (2011, n=9) administered activated autologous T cells armed with bispecific antibodies against CD3 and CD20 (aATC) prior to auto-SCT. Two patients achieved VGPR, two patients achieved CR while five patients developed PR.
Fowler et al. (2016, n=20) used type 1 polarized, rapamycin resistant T (T1-Rapa) cells after auto-SCT in high risk myeloma patients. Out of 19 evaluable patients, 5 had ongoing CR (at 733, 787, 847, 926, 1186 days) while 14 patients had disease progression (from 64 to 917 days). No adverse effects or dose limiting toxicity was observed in any of the patients.
Conclusion
Adoptive cellular therapy has shown excellent clinical activity against myeloma cells in relapsed refractory patients. The adverse events like CRS and infusion reactions are concerning but manageable. The results of trials involving T cells targeting BCMA are very encouraging.

Disclosures
No relevant conflicts of interest to declare.